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ENO1–BACE2-mediated LDLR cleavage promotes liver cancer progression by remodelling cholesterol metabolism
Open accessAbstract
Enolase 1 (ENO1) is a glycolytic enzyme involved in tumour progression that performs a variety of classical and nonclassical functions. However, the mechanism by which it promotes tumour progression is still not fully understood. Here, we found that ENO1 can bind to β-site amyloid precursor protein cleaving enzyme 2 (BACE2), a codependent gene of ENO1, in liver cancer cells. By suppressing lysosomal-dependent degradation, ENO1 stabilizes BACE2 protein level without affecting its messenger RNA level. Further analysis revealed that ENO1 and BACE2 promote low-density lipoprotein receptor (LDLR) cleavage, leading to decreased absorption of exogenous cholesterol. To maintain intracellular cholesterol levels, ENO1 and BACE2 upregulate the expression of genes involved in de novo cholesterol synthesis through a negative feedback mechanism. Both in vitro and in vivo, BACE2 mediates the tumour-promoting effect of ENO1 in liver cancer. Finally, high expression levels of ENO1 and BACE2 and low expression levels of LDLR were detected in clinical hepatocellular carcinoma samples, and abnormal expression of the ENO1–BACE2–LDLR axis was significantly associated with poor prognosis in patients with liver cancer. These data collectively demonstrated that ENO1 functions in protein cleavage by binding to BACE2 and promotes liver cancer progression by reprogramming cholesterol metabolism.
Overview
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Written from the paper’s full text.
TL;DR
ENO1 binds BACE2 in liver cancer cells, stabilizes BACE2 by suppressing its lysosomal degradation, and together they cleave LDLR to reduce exogenous cholesterol uptake while upregulating de novo cholesterol synthesis. This ENO1–BACE2–LDLR axis promotes liver cancer proliferation and tumor growth and is associated with poor prognosis in HCC.
Key findings
- DepMap analysis identified BACE2 as a codependent gene of ENO1; co-IP and proximity ligation assays confirmed ENO1–BACE2 interaction in liver cancer cells, including Huh7, PLC, Hep3B, and HepG2.
- ENO1 knockdown decreased BACE2 protein without affecting BACE2 mRNA; BACE2 degradation was partially rescued by chloroquine and NH4Cl but not MG132, indicating lysosomal/autolysosome-dependent regulation.
- BACE2 overexpression decreased full-length LDLR and increased N-terminal shed and C-terminal LDLR fragments; ENO1 knockdown increased full-length LDLR and decreased N-terminal fragment. BACE2 overexpression reduced Dil-LDL uptake, increased medium LDL-C, increased intracellular total cholesterol, and upregulated cholesterol synthesis genes including HMGCR, SQLE, NSDHL, DHCR7, MVK, and CYP51A1; BACE2 knockdown suppressed these genes.
- In vivo, ENO1 knockdown suppressed tumor growth and weight, while BACE2 overexpression rescued these effects. In clinical samples, ENO1 and BACE2 were upregulated and LDLR downregulated in HCC; IHC in 73 paired cases showed elevated ENO1 and BACE2 and a strong positive correlation between them, and high ENO1/BACE2 or low LDLR was associated with poorer survival.
Methods
- Cell-based assays in HEK293T, Hep3B, Huh7, HepG2, and PLC cells: co-IP, PLA, western blotting, qPCR, cell growth/crystal violet staining, Dil-LDL uptake, intracellular total cholesterol, and extracellular LDL-C measurements.
- Xenograft experiments: PLC cells stably expressing NTC or shENO1 with or without BACE2 overexpression were injected subcutaneously into 4-week-old male nude mice (n = 5 per group); tumor size was measured every 3 days.
- Clinical and bioinformatic analyses: paired HCC and adjacent noncancerous tissues were analyzed by qPCR (16 pairs), western blotting (7 pairs), and IHC tissue microarray (73 pairs); DepMap, GEPIA 2, and Kaplan–Meier Plotter were used for codependency, correlation, and survival analyses.
Limitations
- The paper does not state a limitations section. Evident from the text: the LDLR cleavage site was not mapped; the authors predict it may be the EGF precursor homology domain C based on an ∼95 kDa N-terminal fragment, requiring further validation.
- Clinical validation relies on relatively small cohorts (16 qPCR pairs, 7 western blot pairs, 73 IHC pairs) and public survival analyses, so the ENO1–BACE2–LDLR associations are correlative.
- Functional work is largely in liver cancer cell lines and subcutaneous nude-mouse xenografts; no patient-derived models, in vivo cleavage-site validation, or therapeutic targeting of the axis is reported.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
1 of 29 cited sources checked · 1 supported · 0 flagged
- Findingown data
ENO1 knockdown-induced degradation of BACE2 was partially inhibited by the autophagy inhibitor chloroquine and the lysosomal inhibitor NH4Cl but not the proteasome inhibitor MG132.
“As shown in Figure 2C–E, ENO1 knockdown-induced degradation of BACE2 was partially inhibited by the autophagy inhibitor chloroquine and the lysosomal inhibitor NH4Cl but not the proteasome inhibitor MG132.”
Quote in the paperSubstantial claim - Findingown data
BACE2 knockdown had little effect on ENO1 protein levels in PLC and Huh7 cells.
“Western blot analysis revealed that ENO1 knockdown significantly suppressed BACE2 protein levels (Figure 2A), while BACE2 knockdown had little effect on ENO1 protein levels (Figure 2B) in PLC and Huh7 cells.”
Quote in the paperSubstantial claim - Findingown data
DepMap analysis revealed codependent genes of ENO1, with the top 10 genes being UNKL, TMEM176B, FAM181B, AGBL3, BACE2, MORC3, USP40, TRIM36, GAPDH, and SYT9.
“DepMap analysis revealed codependent genes of ENO1, and the top 10 genes were UNKL, TMEM176B, FAM181B, AGBL3, BACE2, MORC3, USP40, TRIM36, GAPDH, and SYT9 (Figure 1A).”
Quote in the paperSubstantial claim - Findingown data
ENO1 knockdown significantly suppressed BACE2 protein levels in PLC and Huh7 cells.
“Western blot analysis revealed that ENO1 knockdown significantly suppressed BACE2 protein levels (Figure 2A), while BACE2 knockdown had little effect on ENO1 protein levels (Figure 2B) in PLC and Huh7 cells.”
Quote in the paperSubstantial claim - Findingown data
ENO1 binds to BACE2 in liver cancer cells.
“The results clearly demonstrated that Flag-tagged BACE2 interacted with GFP-tagged ENO1 in 293T cells (Figure 1E).”
- Also stated in: § ENO1 binds to BACE2 in liver cancer cells · plain
“Similar results were also observed in different liver cancer cell lines, including Huh7, PLC, Hep3B, and HepG2 (Figure 1F; Supplementary Figure S1B and C).”
- Also stated in: § ENO1 binds to BACE2 in liver cancer cells · hedged
“These data support that ENO1 interacts with BACE2 at endogenous protein level.”
Quote in the paperSubstantial claim - Also stated in: § ENO1 binds to BACE2 in liver cancer cells · plain
- Findingown data
Comprehensive analysis of correlation between expression levels of the codependent genes and ENO1 in liver cancer and association with HCC prognosis revealed GAPDH, BACE2, and TRIM36 as the top 3 genes.
“A comprehensive analysis of the correlation between expression levels of these genes and ENO1 in liver cancer (Figure 1B; Tang et al., 2017) as well as the association between high or low expression level of these genes and hepatocellular carcinoma (HCC) prognosis (Figure 1C; Menyhart et al., 2018) revealed that GAPDH, BACE2, and TRIM36 were the top 3 genes (Figure 1D; Supplementary Figure S1A).”
Quote in the paperSubstantial claim0 of 2 sources checked - Findingown data
BACE2 mRNA levels remained consistent when ENO1 was knocked down.
“Further quantitative polymerase chain reaction (qPCR) analysis revealed that BACE2 mRNA levels remained consistent when ENO1 was knocked down, suggesting that ENO1 regulates BACE2 protein expression at the posttranscriptional level (Supplementary Figure S2A and B).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of ENO1 increased the cellular cholesterol level.
“The overexpression of ENO1 increased the cellular cholesterol level (Figure 5A).”
Quote in the paperSubstantial claim - Findingown data
BACE2 protein levels markedly increased in liver cancer tissues compared with paracarcinoma tissues.
“Western blot analysis of ENO1, BACE2, and LDLR protein levels showed consistent results that ENO1 and BACE2 protein levels markedly increased, while LDLR protein levels decreased in liver cancer tissues compared with paracarcinoma tissues (Figure 6B).”
Quote in the paperSubstantial claim - Findingown data
ENO1 knockdown suppressed the expression of cholesterol biosynthetic genes HMGCR, SQLE, DHCR7, MVK, and CYP51A1.
“Consistently, ENO1 knockdown suppressed the expression of cholesterol biosynthetic genes (HMGCR, SQLE, DHCR7, MVK, and CYP51A1) (Figure 5B).”
Quote in the paperSubstantial claim - Findingcitation
By analysing Stützer et al. published data, LDLR was identified as a potential substrate of BACE2.
“By analysing their published data, we identified an interesting protein, LDLR, as a potential substrate of BACE2.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Stützer et al. (2013) source
- Findingown data
qPCR analysis of mRNA levels of cholesterol synthetic genes in tumours showed that overexpression of BACE2 could partially reverse ENO1 knockdown-induced suppression of cholesterol-related gene expression.
“qPCR analysis of mRNA levels of cholesterol synthetic genes in these tumours showed that overexpression of BACE2 could partially reverse ENO1 knockdown-induced suppression of cholesterol-related gene expression (Figure 5I).”
Quote in the paperSubstantial claim - Findingown data
Knockdown of BACE2 significantly increased the total protein level of endogenous LDLR in Huh7 and PLC cells.
“Indeed, overexpression of BACE2 significantly decreased whereas knockdown of BACE2 significantly increased the total protein level of endogenous LDLR in Huh7 and PLC cells (Figure 3A and B).”
Quote in the paperSubstantial claim - Findingown data
ENO1 knockdown decreased BACE2 expression at the endogenous level.
“At the endogenous level, ENO1 knockdown decreased BACE2 expression but increased LDLR expression (Figure 3G).”
Quote in the paperSubstantial claim - Findingown data
ENO1 knockdown increased LDLR protein levels in PLC cells.
“In addition, ENO1 knockdown decreased BACE2 levels, increased LDLR protein levels, and significantly suppressed cell proliferation (Figure 5C), which were all reversed when we further overexpressed BACE2 in ENO1-knockdown cells (Figure 5C).”
Quote in the paperSubstantial claim - Findingown data
ENO1 knockdown increased LDLR expression at the endogenous level.
“At the endogenous level, ENO1 knockdown decreased BACE2 expression but increased LDLR expression (Figure 3G).”
Quote in the paperSubstantial claim - Findingown data
BACE2 overexpression promoted the accumulation of total cholesterol.
“Interestingly, BACE2 overexpression promoted the accumulation of total cholesterol (Figure 4E).”
Quote in the paperSubstantial claim - Findingown data
ENO1 protein levels markedly increased in liver cancer tissues compared with paracarcinoma tissues.
“Western blot analysis of ENO1, BACE2, and LDLR protein levels showed consistent results that ENO1 and BACE2 protein levels markedly increased, while LDLR protein levels decreased in liver cancer tissues compared with paracarcinoma tissues (Figure 6B).”
Quote in the paperSubstantial claim - Findingown data
BACE2 overexpression inhibits the uptake of exogenous cholesterol, as shown by lower Dil-LDL fluorescence intensity in BACE2-overexpressing cells than in EV control cells.
“The fluorescence intensity in BACE2-overexpressing cells was lower than that in EV control cells (Figure 4C), indicating that BACE2 inhibits the uptake of exogenous cholesterol.”
Quote in the paperSubstantial claim - Findingown data
ENO1 mRNA levels were upregulated in liver cancer tissues compared with paracarcinoma tissues.
“By analysing ENO1, BACE2, and LDLR mRNA levels in paired clinical HCC lesions and adjacent noncancerous tissue samples, we found that ENO1 and BACE2 mRNA levels were upregulated, whereas LDLR mRNA levels were downregulated in liver cancer tissues compared with paracarcinoma tissues (Figure 6A).”
Quote in the paperSubstantial claim - Findingown data
BACE2 mRNA levels were upregulated in liver cancer tissues compared with paracarcinoma tissues.
“By analysing ENO1, BACE2, and LDLR mRNA levels in paired clinical HCC lesions and adjacent noncancerous tissue samples, we found that ENO1 and BACE2 mRNA levels were upregulated, whereas LDLR mRNA levels were downregulated in liver cancer tissues compared with paracarcinoma tissues (Figure 6A).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of BACE2 significantly decreased the total protein level of endogenous LDLR in Huh7 and PLC cells.
“Indeed, overexpression of BACE2 significantly decreased whereas knockdown of BACE2 significantly increased the total protein level of endogenous LDLR in Huh7 and PLC cells (Figure 3A and B).”
Quote in the paperSubstantial claim - Findingown data
BACE2 overexpression rescued ENO1 knockdown-induced defects in tumour growth and tumour incidence.
“Moreover, BACE2 overexpression obviously rescued ENO1 knockdown-induced defects in tumour growth and tumour incidence (Figure 5E–G).”
Quote in the paperSubstantial claim - Findingown data
ENO1 knockdown decreased BACE2 levels in PLC cells.
“In addition, ENO1 knockdown decreased BACE2 levels, increased LDLR protein levels, and significantly suppressed cell proliferation (Figure 5C), which were all reversed when we further overexpressed BACE2 in ENO1-knockdown cells (Figure 5C).”
Quote in the paperSubstantial claim - Findingown data
LDLR mRNA levels were downregulated in liver cancer tissues compared with paracarcinoma tissues.
“By analysing ENO1, BACE2, and LDLR mRNA levels in paired clinical HCC lesions and adjacent noncancerous tissue samples, we found that ENO1 and BACE2 mRNA levels were upregulated, whereas LDLR mRNA levels were downregulated in liver cancer tissues compared with paracarcinoma tissues (Figure 6A).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of BACE2 dramatically reversed ENO1 knockdown-induced suppression of cholesterol biosynthetic gene expression.
“Furthermore, the overexpression of BACE2 dramatically reversed ENO1 knockdown-induced suppression of cholesterol biosynthetic gene expression (Figure 5D), indicating that ENO1 promotes cholesterol synthesis through BACE2.”
Quote in the paperSubstantial claim - Findingown data
Western blot analysis confirmed protein levels of ENO1 and BACE2, as well as the regulation pattern of LDLR protein level by ENO1 and BACE2, in tumour lysates.
“Western blot analysis further confirmed protein levels of ENO1 and BACE2, as well as the regulation pattern of LDLR protein level by ENO1 and BACE2, in tumour lysates (Figure 5H).”
Quote in the paperSubstantial claim - Findingown data
ENO1 knockdown significantly suppressed cell proliferation in PLC cells.
“In addition, ENO1 knockdown decreased BACE2 levels, increased LDLR protein levels, and significantly suppressed cell proliferation (Figure 5C), which were all reversed when we further overexpressed BACE2 in ENO1-knockdown cells (Figure 5C).”
Quote in the paperSubstantial claim - Findingown data
In vivo xenograft experiments demonstrated that ENO1 knockdown suppressed tumour growth.
“In vivo xenograft experiments demonstrated that ENO1 knockdown suppressed tumour growth, whereas BACE2 overexpression promoted tumour growth and increased tumour weight (Figure 5E–G).”
Quote in the paperSubstantial claim - Findingown data
BACE2high/LDLRhigh patients had poorer prognoses than BACE2low/LDLRhigh patients.
“Moreover, BACE2high/LDLRhigh patients had poorer prognoses than BACE2low/LDLRhigh patients (Figure 6G left panel), but there was no difference in survival probability between BACE2high/LDLRlow and BACE2low/LDLRlow patients (Figure 6G right panel).”
Quote in the paperSubstantial claim - Findingown data
LDLR protein levels decreased in liver cancer tissues compared with paracarcinoma tissues.
“Western blot analysis of ENO1, BACE2, and LDLR protein levels showed consistent results that ENO1 and BACE2 protein levels markedly increased, while LDLR protein levels decreased in liver cancer tissues compared with paracarcinoma tissues (Figure 6B).”
Quote in the paperSubstantial claim - Findingown data
There was no difference in survival probability between BACE2high/ENO1low and BACE2low/ENO1low patients.
“Furthermore, BACE2high/ENO1high patients had poorer prognoses than BACE2low/ENO1high patients (Figure 6F left panel), but there was no difference in survival probability between BACE2high/ENO1low and BACE2low/ENO1low patients (Figure 6F right panel).”
Quote in the paperSubstantial claim - Findingown data
There is a strong positive correlation between ENO1 and BACE2 protein levels in clinicopathologically characterized liver cancer samples.
“Quantitative analysis revealed the elevated expressions of ENO1 and BACE2 (Figure 6C and D) and a strong positive correlation between ENO1 and BACE2 protein levels in clinicopathologically characterized liver cancer samples (Figure 6E).”
Quote in the paperSubstantial claim - Findingreasoning
ENO1 activates genes involved in de novo cholesterol synthesis through BACE2.
“ENO1 activates genes involved in de novo cholesterol synthesis through BACE2”
Quote in the paperSubstantial claim - Findingown data
HCC patients with low levels of BACE2 or ENO1 or high levels of LDLR in their liver cancer lesions survived longer.
“Survival curves generated via Kaplan–Meier Plotter (liver cancer) revealed that HCC patients with low levels of BACE2 or ENO1 or high levels of LDLR in their liver cancer lesions survived longer (Figure 1C; Supplementary Figure S4A and B), suggesting that the ENO1–BACE2–LDLR axis could represent promising prognostic biomarkers in patients with liver cancer.”
Quote in the paperSubstantial claim - Findingown data
IHC quantitative analysis revealed elevated expression of BACE2 in clinicopathologically characterized liver cancer samples.
“Quantitative analysis revealed the elevated expressions of ENO1 and BACE2 (Figure 6C and D) and a strong positive correlation between ENO1 and BACE2 protein levels in clinicopathologically characterized liver cancer samples (Figure 6E).”
Quote in the paperSubstantial claim - Findingown data
BACE2high/ENO1high patients had poorer prognoses than BACE2low/ENO1high patients.
“Furthermore, BACE2high/ENO1high patients had poorer prognoses than BACE2low/ENO1high patients (Figure 6F left panel), but there was no difference in survival probability between BACE2high/ENO1low and BACE2low/ENO1low patients (Figure 6F right panel).”
Quote in the paperSubstantial claim - Findingown data
IHC quantitative analysis revealed elevated expression of ENO1 in clinicopathologically characterized liver cancer samples.
“Quantitative analysis revealed the elevated expressions of ENO1 and BACE2 (Figure 6C and D) and a strong positive correlation between ENO1 and BACE2 protein levels in clinicopathologically characterized liver cancer samples (Figure 6E).”
Quote in the paperSubstantial claim - Findingown data
There was no difference in survival probability between BACE2high/LDLRlow and BACE2low/LDLRlow patients.
“Moreover, BACE2high/LDLRhigh patients had poorer prognoses than BACE2low/LDLRhigh patients (Figure 6G left panel), but there was no difference in survival probability between BACE2high/LDLRlow and BACE2low/LDLRlow patients (Figure 6G right panel).”
Quote in the paperSubstantial claim - Findingnone given
BACE2 is a potential codependent gene of ENO1.
“BACE2, a potential codependent gene of ENO1”
Quote in the paperNot a substantial claim - Findingown data
ENO1 interacts with BACE2.
“we found that ENO1 interacts with BACE2”
Quote in the paperSubstantial claim - Findingnone given
Ectopic expression of the ENO1-BACE2-LDLR axis in liver cancer tissues is significantly correlated with prognosis.
“Ectopic expression of the ENO1–BACE2–LDLR axis in liver cancer tissues and its significant correlation with prognosis”
Quote in the paperSubstantial claim - Findingown data
The N-terminal fragment of LDLR is ∼95 kDa.
“Our results revealed that the N-terminal fragment of LDLR is ∼95 kDa”
Quote in the paperSubstantial claim - Findingown data
ENO1 can also bind to its protein partner BACE2 to further participate in regulating protein cleavage in liver cancer cells.
“we found that ENO1 can also bind to its protein partner BACE2 to further participate in regulating protein cleavage in liver cancer cells”
Quote in the paperSubstantial claim - Interpretationown data
ENO1 regulates BACE2 protein expression at the posttranscriptional level.
“Further quantitative polymerase chain reaction (qPCR) analysis revealed that BACE2 mRNA levels remained consistent when ENO1 was knocked down, suggesting that ENO1 regulates BACE2 protein expression at the posttranscriptional level (Supplementary Figure S2A and B).”
Quote in the paperSubstantial claim - Interpretationown data
ENO1 promotes cholesterol synthesis through BACE2.
“Furthermore, the overexpression of BACE2 dramatically reversed ENO1 knockdown-induced suppression of cholesterol biosynthetic gene expression (Figure 5D), indicating that ENO1 promotes cholesterol synthesis through BACE2.”
Quote in the paperSubstantial claim - Interpretationown data
ENO1 promotes the accumulation of cellular cholesterol by activating cholesterol synthesis.
“These data indicate that ENO1 promotes the accumulation of cellular cholesterol by activating cholesterol synthesis.”
Quote in the paperSubstantial claim - Interpretationown data
LDLR is cleaved by BACE2 in liver cancer cells.
“These data suggest that LDLR is indeed cleaved by BACE2 in liver cancer cells.”
Quote in the paperSubstantial claim - Interpretationown data
BACE2 promotes cellular cholesterol synthesis through negative feedback caused by LDLR cleavage.
“Collectively, we concluded that BACE2 promotes cellular cholesterol synthesis through negative feedback caused by LDLR cleavage.”
Quote in the paperSubstantial claim - Interpretationown data
ENO1 promotes BACE2 protein stabilization by suppressing the autolysosome pathway.
“These results indicate that ENO1 promotes BACE2 protein stabilization by suppressing the autolysosome pathway.”
Quote in the paperSubstantial claim - Interpretationown data
The findings provide the first evidence of the protein cleavage function of ENO1.
“Our findings provide the first evidence of the protein cleavage function of ENO1”
Quote in the paperSubstantial claim - Interpretationown data
ENO1 stabilizes BACE2 protein level by suppressing its lysosomal-dependent protein degradation.
“ENO1 stabilizes BACE2 protein level by suppressing its lysosomal-dependent protein degradation.”
Quote in the paperSubstantial claim - Interpretationown data
The ENO1-BACE2-LDLR axis could represent promising prognostic biomarkers in patients with liver cancer.
“Survival curves generated via Kaplan–Meier Plotter (liver cancer) revealed that HCC patients with low levels of BACE2 or ENO1 or high levels of LDLR in their liver cancer lesions survived longer (Figure 1C; Supplementary Figure S4A and B), suggesting that the ENO1–BACE2–LDLR axis could represent promising prognostic biomarkers in patients with liver cancer.”
Quote in the paperSubstantial claim - Interpretationown data
The ENO1-BACE2-LDLR axis plays a role in liver cancer progression.
“demonstrate the role of the ENO1–BACE2–LDLR axis in liver cancer progression”
Quote in the paperSubstantial claim - Interpretationreasoning
The ENO1-BACE2 interaction promotes liver cancer progression.
“We reveal a potential mechanism by which the ENO1–BACE2 interaction promotes liver cancer progression”
Quote in the paperSubstantial claim - Interpretationown data
Targeting the ENO1-BACE2-LDLR axis may be an effective approach for treating liver cancer.
“indicate that targeting this axis may be an effective approach for treating liver cancer”
Quote in the paperNot a substantial claim
- Probably not a substantial claim. 25
- It may state two separate claims as one. 31
- The quote only partly states this claim. 1
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe mature LDLR protein contains 839 amino acids.
“The mature LDLR protein contains 839 amino acids”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Sudhof et al., 1985 source
It may state two separate claims as one.
Findingown dataOverexpression of BACE2 reversed the ENO1 knockdown-induced decrease in BACE2 levels, increase in LDLR protein levels, and suppression of cell proliferation in PLC cells.
“In addition, ENO1 knockdown decreased BACE2 levels, increased LDLR protein levels, and significantly suppressed cell proliferation (Figure 5C), which were all reversed when we further overexpressed BACE2 in ENO1-knockdown cells (Figure 5C).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn BACE2-overexpressing cells, the abundance of full-length LDLR was downregulated, whereas the abundances of N-terminal fragments of LDLR in the supernatant and C-terminal fragments in cell lysates were both upregulated.
“The results showed that in BACE2-overexpressing cells, the abundance of full-length LDLR was downregulated, whereas abundances of N-terminal fragments of LDLR in the supernatant and C-terminal fragments in cell lysates were both upregulated (Figure 3C–F).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataLDL-C content in the cell culture medium of BACE2-overexpressing cells was greater than in EV control cells, indicating an impaired ability of BACE2-overexpressing cells to take up LDL-C.
“Additionally, the low-density lipoprotein cholesterol (LDL-C) content in the cell culture medium of BACE2-overexpressing cells was greater than that in EV control cells (Figure 4D), indicating an impaired ability of BACE2-overexpressing cells to take up LDL-C.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataBACE2 overexpression promoted tumour growth and increased tumour weight in vivo.
“In vivo xenograft experiments demonstrated that ENO1 knockdown suppressed tumour growth, whereas BACE2 overexpression promoted tumour growth and increased tumour weight (Figure 5E–G).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataWhen ENO1 was knocked down in PLC cells overexpressing Flag-N-LDLR, the abundance of full-length LDLR in cell lysates increased, while that of N-terminal fragments in the supernatant decreased.
“Similarly, when ENO1 was knocked down in PLC cells overexpressing Flag-N-LDLR, the abundance of full-length LDLR in cell lysates increased, while that of N-terminal fragments in the supernatant decreased (Figure 3H).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataENO1 promotes BACE2 protein stabilization without affecting its mRNA level.
“promotes BACE2 protein stabilization without affecting its mRNA level”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataENO1 and BACE2 are codependent genes that bind to each other at the protein level in liver cancer cells.
“Overall, we found that ENO1 and BACE2 are codependent genes that bind to each other at the protein level in liver cancer cells.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataENO1 can promote LDLR protein cleavage, resulting in decreased uptake of exogenous cholesterol.
“ENO1 can promote LDLR protein cleavage, resulting in decreased uptake of exogenous cholesterol”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataBACE2 is a codependent gene of ENO1 and interacts with ENO1 at the protein level.
“BACE2 is a codependent gene of ENO1 and interacts with ENO1 at the protein level”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataBACE2, a codependent gene and protein partner of ENO1, functions as an oncogene by promoting liver cancer cell proliferation and tumour progression through its cleavage enzyme function.
“we found that BACE2, a codependent gene and protein partner of ENO1, functions as an oncogene by promoting liver cancer cell proliferation and tumour progression through its cleavage enzyme function”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataENO1 promotes protein stabilization of BACE2, a membrane protease, and further cleaves the membrane protein LDLR.
“ENO1 promotes protein stabilization of BACE2, a membrane protease, and further cleaves the membrane protein LDLR”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationENO1 is a multifunctional protein that promotes the Warburg effect as a classical glycolytic enzyme and also acts as a plasminogen receptor and DNA-binding protein.
“ENO1 is a multifunctional protein that not only promotes the Warburg effect as a classical glycolytic enzyme but also acts as a plasminogen receptor and DNA-binding protein (Miles et al., 1991; Ray and Miller, 1991).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim. It may state two separate claims as one.
PremisecitationLDLR is a receptor normally localized to the cell membrane, where it binds cholesterol-rich LDLs and mediates their entry into cells.
“LDLR is a receptor normally localizd to the cell membrane, where it binds to cholesterol-rich LDLs and mediates their entry into cells (Catapano, 1989).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Catapano, 1989 source
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationLDLR plays an inhibitory role in liver cancer and blocking LDLR expression promoted liver cancer progression by reprogramming cholesterol synthesis.
“Previous studies have shown that LDLR plays an inhibitory role in liver cancer and blocking LDLR expression promoted liver cancer progression by reprogramming cholesterol synthesis (Chen et al., 2021a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chen et al., 2021a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationBACE2 is an aspartic protease whose classic function is to cleave APP.
“BACE2 is an aspartic protease whose classic function is to cleave APP (Farzan et al., 2000).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Farzan et al., 2000 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationProteins encoded by codependent genes often interact with each other.
“Proteins encoded by codependent genes often interact with each other, such as the epigenetic codependent MLL and Menin (Fiskus et al., 2022, 2023) as well as MOZ and the Menin–MLL complex (Hemming et al., 2022).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Fiskus et al., 2022, 2023
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Hemming et al., 2022 source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThe ubiquitin-proteasome system and autophagy-lysosome system are two major quality control systems responsible for protein degradation.
“The ubiquitin–proteasome system and autophagy–lysosome system are two major quality control systems responsible for protein degradation (Pohl and Dikic, 2019).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Pohl and Dikic, 2019 source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationENO1 can act as an RNA-binding protein to promote mRNA degradation of IRP1 or mRNA translation of YAP1, thereby suppressing ferroptosis and enhancing arachidonic acid metabolism, leading to tumour progression.
“We recently reported that ENO1 can act as an RNA-binding protein to promote the messenger RNA (mRNA) degradation of iron-regulating protein (IRP1) or mRNA translation of yes-associated protein (YAP1), thereby suppressing ferroptosis and enhancing arachidonic acid metabolism, leading to tumour progression (Zhang et al., 2022a; Sun et al., 2023).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Zhang et al., 2022a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Sun et al., 2023 source
It may state two separate claims as one.
Interpretationown dataBoth ENO1 and BACE2 inhibit LDLR expression through protein cleavage.
“Collectively, these data suggest that both ENO1 and BACE2 inhibit LDLR expression through protein cleavage.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataENO1 promotes cholesterol synthesis and liver cancer progression through BACE2 in vivo.
“Collectively, these data suggest that ENO1 promotes cholesterol synthesis and liver cancer progression through BACE2 in vivo.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationENO1, as a moonlighting protein, performs multiple biological functions in cancer development, such as gene regulation, protein synthesis, cascade signalling pathway activation, immune responses, host-pathogen interactions, chemotherapy resistance, and cellular stress responses.
“ENO1, as a moonlighting protein, performs multiple biological functions in cancer development”
Quote in the paperNot a substantial claim0 of 3 sources checkedIt may state two separate claims as one.
Interpretationown dataENO1 and BACE2 promote the cleavage of LDLR and suppress the absorption of exogenous cholesterol.
“ENO1 and BACE2 further promote the cleavage of LDLR and suppress the absorption of exogenous cholesterol.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
InterpretationreasoningActivation of de novo cholesterol synthesis by ENO1 through BACE2 accelerates cell proliferation by promoting intracellular cholesterol accumulation.
“accelerating cell proliferation by promoting intracellular cholesterol accumulation”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationreasoningENO1 activates cholesterol biosynthesis through BACE2, ultimately promoting intracellular cholesterol accumulation and liver cancer progression.
“As a negative feedback mechanism, ENO1 then activates cholesterol biosynthesis through BACE2, ultimately promoting intracellular cholesterol accumulation and liver cancer progression (Figure 7).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenThe experiments were independently repeated three times with similar results.
“The experiments were independently repeated three times with similar results.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataENO1 can reprogramme cholesterol metabolism through a protein cleavage role, in addition to regulating the Warburg effect.
“In the present study, we demonstrated that, in addition to regulating the Warburg effect, the glycolytic enzyme ENO1 can reprogramme cholesterol metabolism through an unrecognized role of protein cleavage.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationAberrant expression of ENO1 has been reported in a variety of cancers and is associated with poor tumour prognosis.
“Aberrant expression of ENO1 has been reported in a variety of cancers and is associated with poor tumour prognosis”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationENO1 binds to and promotes the translation of YAP1 mRNA, promoting liver carcinogenesis by activating arachidonic acid metabolism and PGE2 accumulation.
“ENO1 binds to and promotes the translation of YAP1 mRNA, promoting liver carcinogenesis by activating arachidonic acid metabolism and PGE2 accumulation”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sun et al., 2023 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe LDLR structure from the N-terminus to the C-terminus includes seven ligand-binding domain repeats, an epidermal growth factor (EGF) precursor homology domain, an O-linked sugar domain, a transmembrane domain, and a cytoplasmic domain.
“The LDLR structure from the N-terminus to the C-terminus includes seven ligand-binding domain repeats, an epidermal growth factor (EGF) precursor homology domain, an O-linked sugar domain, a transmembrane domain, and a cytoplasmic domain”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Brown and Goldstein, 1986 source
Probably not a substantial claim. The paper may give no reason why it holds.
Premisenone givenBACE2's role in liver cancer has not been reported.
“its role in liver cancer has not been reported”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationBACE2 regulates signalling pathways including Yap, STAT3, NF-κB, and Ca2+ influx, rather than performing its classical cleavage enzyme function, in these studies.
“BACE2 regulates signalling pathways including Yap (Matafora et al., 2020), STAT3 (Chen et al., 2021b), NF-κB (Wang et al., 2020), and Ca2+ influx (He et al., 2021), rather than performing its classical cleavage enzyme function, in these studies”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationENO1 binds to and degrades IRP1 mRNA, thereby regulating the metabolic homeostasis of iron ions in cells, inhibiting ferroptosis, and promoting the occurrence and development of liver cancer.
“ENO1 binds to and degrades IRP1 mRNA, thereby regulating the metabolic homeostasis of iron ions in cells, inhibiting ferroptosis, and promoting the occurrence and development of liver cancer”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zhang et al., 2022a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Interpretationown dataThe LDLR cleavage site by BACE2 may be the EGF precursor homology domain C.
“we predict that the LDLR cleavage site by BACE2 may be the EGF precursor homology domain C”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationMonoclonal antibodies block the interaction between PCSK9 and EGF-A, significantly reducing plasma LDL-C levels.
“monoclonal antibodies block the interaction between PCSK9 and EGF-A, significantly reducing plasma LDL-C levels”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Stein and Raal, 2014 source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationIn liver cancer and colorectal cancer, PCSK9 inhibitors suppress metabolism and growth of cancer cells, suggesting that PCSK9 is a therapeutic target for cancer treatment.
“in liver cancer and colorectal cancer, PCSK9 inhibitors suppress metabolism and growth of cancer cells, suggesting that PCSK9 is a therapeutic target for cancer treatment”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim. It may be too vague to check against evidence.
InterpretationreasoningThe findings of the codependency and interaction between ENO1 and BACE2 shed new light on their coordinated and versatile role in cholesterol metabolism and liver cancer progression.
“the findings of the codependency and interaction between ENO1 and BACE2 shed new light on their coordinated and versatile role in cholesterol metabolism and liver cancer progression”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
Premisenone givenBACE2 is abnormally expressed in a variety of cancers and plays a role in promoting tumour progression.
“BACE2 is abnormally expressed in a variety of cancers and plays a role in promoting tumour progression”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenThe studies were conducted in accordance with the ethical guidelines of the Declaration of Helsinki and the Declaration of Istanbul.
“The studies were conducted in accordance with the ethical guidelines of the Declaration of Helsinki and the Declaration of Istanbul”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAll animal experiments and procedures were approved by the Animal Research Ethics Committee of South China University of Technology (AEC number 2024060).
“approved by the Animal Research Ethics Committee of South China University of Technology (AEC number 2024060)”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenWritten informed consent and approval from each participant were obtained from the Institutional Research Ethics Committee of the First Affiliated Hospital of the University of Science and Technology of China.
“written informed consent and approval from each participant were obtained from the Institutional Research Ethics Committee of the First Affiliated Hospital of the University of Science and Technology of China”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAll animal experiments and procedures were performed in compliance with ethical regulations.
“All animal experiments and procedures were performed in compliance with ethical regulations”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The codependent genes and interacting proteins of ENO1 and how they synergistically participate in the tumour process remain unclear.
“However, the codependent genes and interacting proteins of ENO1 and how they synergistically participate in the tumour process remain unclear.”
The paper relies on this without support.
Whether and how BACE2 regulates liver cancer progression are largely unknown.
“However, whether and how BACE2, a β-secretase that functions in Alzheimer's disease (AD), regulates liver cancer progression are largely unknown.”
The paper relies on this without support.
Other substrates and the potential role of BACE2 in tumours through its cleavage function are largely unknown.
“However, other substrates and the potential role of BACE2 in tumours through its cleavage function are largely unknown.”
The paper relies on this without support.
The function of BACE2 in cancer, especially liver cancer, is largely unknown.
“However, the function of BACE2 in cancer, especially liver cancer, is largely unknown.”
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Self-citation
Metadata
- Authors
- Li, Z., Fan, K., Suo, C., Gu, X., Zhu, C., Wei, H., Chen, L., Gao, P., & Sun, L.
- Affiliations
- South China University of Technology (CN)
- Guangdong Academy of Medical Sciences (CN)
- Guangzhou First People's Hospital (CN)
- University of Science and Technology of China (CN)
- Corresponding author
- Gao, Ping
- Sun, Linchong
- Venue
- Journal of Molecular Cell Biology
- Publisher
- Oxford University Press (OUP)
- Published
- 2025-01
- Volume
- 17
- Issue
- 1
- ISSN
- 1674-2788 (ISSN-L)
- 1759-4685
- PMC
- PMC12246778
- OpenAlex
- W4407265697
- Cited by
- 13
- References
- 49
- Citations by year
- 2026: 11 · 2025: 2
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Molecular Cell Biology (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (82422057, 82273221, 82341013)
- Guangzhou Municipal Science and Technology Bureau (2024A04J6493)
- Young Scholars of Southern Medical University (G623281133)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- alpha-enolase, BACE2, liver cancer, hepatocellular carcinoma, cholesterol metabolism, lysosomal degradation, protein stabilization, de novo cholesterol synthesis, tumor progression, prognosis
- MeSH terms
- Animals, Cholesterol, DNA-Binding Proteins, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Phosphopyruvate Hydratase, Receptors, LDL, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Disease Progression, Tumor Suppressor Proteins, Cell Line, Tumor, Mice, Amyloid Precursor Protein Secretases, Proteolysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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