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Cited by 36Mechanisms of cancer metastasisHistone Deacetylase Inhibitors ResearchHepatocellular Carcinoma Treatment and Prognosis

Novel HDAC5-interacting motifs of Tbx3 are essential for the suppression of E-cadherin expression and for the promotion of metastasis in hepatocellular carcinoma

Open access
Dong, Liang, Dong, Qi, Chen, Ying, Li, Yichen, Zhang, Bao, Zhou, Fanghang, Lyu, Xiaoming, Chen, George G. +3 more·2018·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-018-0025-6PMC PMC6107554
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Abstract

Tbx3, a transcriptional repressor, is essential in the organogenesis of vertebrates, stem cell self-renewal and differentiation, and the carcinogenesis of multiple tumor types. However, the mechanism by which Tbx3 participates in the metastasis of hepatocellular carcinoma (HCC) remains largely unknown. In this study, we show that Tbx3 was dramatically upregulated in clinical HCC samples and that elevated expression of Tbx3 promoted cancer progression. To determine the underlying mechanism, systematic glycine scan mutagenesis and deletion assays were performed. We identified two critical motifs, 585 LFSYPYT 591 and 604 HRH 606, that contribute to the repression of transcriptional activity. These motifs are also essential for Tbx3 to promote cell migration and metastasis both in vitro and in vivo via the suppression of E-cadherin expression. More importantly, Tbx3 directly interacts with HDAC5 via these motifs, and an HDAC inhibitor blocks Tbx3-mediated cell migration and the downregulation of E-cadherin in HCC. As Tbx3 is involved in the carcinogenesis of multiple types of human cancers, our findings suggest an important target for anti-cancer drug development.

AI snapshot

Written from the paper’s full text.

TL;DR

In hepatocellular carcinoma, Tbx3 is upregulated and promotes progression/metastasis, and two repression-domain motifs—585LFSYPYT591 and 604HRH606—are required for Tbx3-mediated E-cadherin suppression and migration/metastasis. These motifs mediate interaction with HDAC5, and HDAC inhibition blocks Tbx3-driven migration and E-cadherin downregulation.

Key findings

  • Tbx3 protein was upregulated in 8 of 11 paired HCC tumors versus adjacent non-tumor tissues, and ectopic Tbx3 promoted tumor progression in nude mice.
  • Glycine scan/deletion assays identified 585LFSYPYT591 and 604HRH606 as repression motifs: individual mutation reduced repression by 40% and 27%, simultaneous mutation abolished repression, and 588YPYTYMA594/604HRH606 mutation reduced activity by 93%.
  • The motifs were required for migration/metastasis: wild-type Tbx3 promoted metastasis in 7/7 mice, the Tbx3 mutant almost abolished metastasis, and no tumor nodules were observed in controls. E-cadherin was reduced in 50/53 HCCs (94.3%, p < 0.0001), with a negative correlation between Tbx3 and E-cadherin (R = −0.303, p < 0.05).
  • Tbx3 bound HDAC5 via these motifs; binding was reduced by ~80% when 585LFSYPYT591 was mutated, ~30% when 604HRH606 was mutated, and completely lost when both were mutated. Sodium butyrate restored E-cadherin and reduced migration.

Methods

  • Paired primary HCC specimens were collected from 2004–2009 at Prince Wales Hospital, CUHK; western blot used 11 paired tissues, RT-qPCR used 53 primary liver cancer tissues, and the tissue-sample section reports 54 HCC patients. Cell lines included HepG2, Bel7404, and HEK293T.
  • The study used systematic glycine scan mutagenesis and deletion assays, Gal4-RD luciferase reporter assays, RT-qPCR, western blot, co-immunoprecipitation, wound healing, Transwell, immunohistochemistry, and nude mouse metastasis assays.
  • Statistical analysis used paired t-tests, Spearman’s rank correlation, p < 0.05 significance, and SPSS 21.0.

Limitations

  • No explicit limitations section is present in the paper; the paper states none.
  • Evident from the text: clinical analyses rely on modest sample sizes (11 paired tissues for western blot; 53 for RT-qPCR; 54 patients in the tissue-sample section), and the conclusion’s prognostic claim is not supported by a survival analysis in the presented results.
  • Evident from the text: in vivo metastasis experiments use nude mice with HepG2 cells rather than patient-derived models, and mechanistic conclusions rely heavily on cell-line assays.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41392-018-0025-6

Cites

60 of 60 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

11 of 23 cited sources checked · 5 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The Tbx3 repression domain is highly conserved between Tbx2 and Tbx3 in vertebrates.

    “This RD is highly conserved between Tbx2 and Tbx3 in vertebrates.19,35”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [19] He, M., Wen, L., Campbell, C. E., Wu, J. Y. & Rao, Y. Transcription repression by Xenopus ET and its human ortholog TBX3, a gene involved in ulnar-mammary syndrome. Proc. Natl Acad. Sci. USA 96, 10212–10217 (1999). source
    • cites [35] Renard, C. A. et al. Tbx3 is a downstream target of the Wnt/beta-catenin pathway and a critical mediator of beta-catenin survival functions in liver cancer. Cancer Res. 67, 901–910 (2007). source
  • Premisecitation

    Tbx3 is involved in the carcinogenesis of multiple types of human cancers.

    “As Tbx3 is involved in the carcinogenesis of multiple types of human cancers, our findings suggest an important target for anti-cancer drug development.”
    • Also stated in: § Introduction · boosted
      “The fundamental importance of both Tbx3 and Tbx2 has been demonstrated in the self-renewal process of stem cells, in improvements in the germ-line competency of induced pluripotent stem cells (iPS), cellular senescence and oncogenesis of various cancers including head and neck squamous cell carcinoma, gastric, breast, cervical, bladder and liver cancers, as well as melanoma.22–39”
    Quote in the paperNot a substantial claim7 of 10 sources checked
    • cites [22] Amir, S. et al. Regulation of the T-box transcription factor Tbx3 by the tumour suppressor microRNA-206 in breast cancer. Br. J. Cancer 114, 1125–1134 (2016). source
    • cites [23] Arendt, L. M. et al. Human breast progenitor cell numbers are regulated by WNT and TBX3. PLoS ONE 9, e111442 (2014). source

      The Discussion (page unavailable) says TBX3 mutations in breast cancer suggest a possible role in its genesis and reports increased TBX3 activity in various cancer cell lines. It does not establish TBX3 involvement in carcinogenesis across multiple types of human cancer; it says further study is needed even for its role in breast tumors. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [24] Abrahams, A., Mowla, S., Parker, M. I., Goding, C. R. & Prince, S. UV-mediated regulation of the anti-senescence factor Tbx2. J. Biol. Chem. 283, 2223–2230 (2008). source

      The introduction (p. 1) links Tbx3 to several human cancers, including breast, pancreatic, melanoma, bladder, liver, and ovarian cancers. It says these links are primarily based on deregulated expression and describes Tbx3’s contribution to oncogenesis as a possibility, rather than establishing its role in carcinogenesis across those cancer types. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [25] Burgucu, D. et al. Tbx3 represses PTEN and is over-expressed in head and neck squamous cell carcinoma. BMC Cancer 12, 481 (2012). source
    • cites [26] Han, J. et al. Tbx3 improves the germ-line competency of induced pluripotent stem cells. Nature 463, 1096–1100 (2010). source

      The Abstract discusses Tbx3 in mouse stem-cell pluripotency and reprogramming, not its role in human carcinogenesis. Searches for carcinogenesis and human cancers found no passage in our copy addressing the claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [27] Galan-Caridad, J. M. et al. Zfx controls the self-renewal of embryonic and hematopoietic stem cells. Cell 129, 345–357 (2007). source
    • cites [28] Demay, F. et al. T-box factors: targeting to chromatin and interaction with the histone H3 N-terminal tail. Pigment Cell Res. 20, 279–287 (2007). source
    • cites [29] Miao, Z. F. et al. Tbx3 overexpression in human gastric cancer is correlated with advanced tumor stage and nodal status and promotes cancer cell growth and invasion. Virchows Arch. 469, 505–513 (2016). source
    • cites [30] Krstic, M. et al. The transcriptional regulator TBX3 promotes progression from non-invasive to invasive breast cancer. BMC Cancer 16, 671 (2016). source
    • cites [31] Lyng, H. et al. Gene expressions and copy numbers associated with metastatic phenotypes of uterine cervical cancer. BMC Genom. 7, 268 (2006). source

      The Discussion (page not specified) identifies TBX3 as a prognostic gene in cervical cancer and says it probably plays a role in tumor growth and may participate in cell-cycle control. It does not establish TBX3 involvement in carcinogenesis across multiple types of human cancer; its mentions of other cancers concern different genes. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Only 56 residues between Leu558 and Ser623 of Tbx3 are highly conserved among vertebrates with 80% sequence identity.

    “only 56 residues were found to be highly conserved between Leu558 and Ser623 with 80% sequence identity.45”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [45] Lu, J., Li, X. P., Dong, Q., Kung, H. F. & He, M. L. TBX2 and TBX3: the special value for anticancer drug targets. Biochim. Biophys. Acta 1806, 268–274 (2010). source

      The section ‘The T domain and the repression domain (RD)’ says that 56 residues between amino acids 558–623 are highly conserved in an alignment of TBX2 and TBX3 across species. It does not report 80% sequence identity or identify the endpoints as Leu558 and Ser623. Page numbers are unavailable in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Findingown data

    Tbx3 mRNA ratio between tumor and non-tumor tissues is negatively associated with E-cadherin mRNA ratio in clinical HCC samples.

    “we observed that the ratio of the quantity of Tbx3 mRNA between tumor and non-tumor tissues was negatively associated with that of E-cadherin (R = −0.303, p < 0.05) (Fig. 4b)”
    Quote in the paperSubstantial claim
  • Findingown data

    Simultaneous mutation of 585LFSYPYT591 and 604HRH606 completely abolishes Tbx3 transcriptional repression activity.

    “the transcriptional repression activity was completely abolished when 585LFSYPYT591 and 604HRH606 were simultaneously mutated”
    • Also stated in: § Identification of repression motifs by combined mutations · boosted
      “the transcriptional repression activity was completely abolished when 585LFSYPYT591 and 604HRH606 were simultaneously mutated, yet in the case of the 588YPYTYMA594/604HRH606 mutation (MT14), the activity was reduced by 93%”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Tbx3 mutant protein used in assays is properly folded and retains all functions other than the mutated motifs.
  • Classified as probably not a substantial claim. 12
  • May combine two claims. 10
  • The quote only partly states this claim. 2

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tbx3 shares a highly conserved DNA-binding domain and repression domain with Tbx2.

    “It has been shown that Tbx3 shares a highly conserved DNA-binding domain and repression domain (RD) with Tbx2.19–21”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [19] He, M., Wen, L., Campbell, C. E., Wu, J. Y. & Rao, Y. Transcription repression by Xenopus ET and its human ortholog TBX3, a gene involved in ulnar-mammary syndrome. Proc. Natl Acad. Sci. USA 96, 10212–10217 (1999). source
    • cites [20] Coll, M., Seidman, J. G. & Muller, C. W. Structure of the DNA-bound T-box domain of human TBX3, a transcription factor responsible for ulnar-mammary syndrome. Structure 10, 343–356 (2002). source
    • cites [21] Carlson, H., Ota, S., Campbell, C. E. & Hurlin, P. J. A dominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: relevance to mutations in Tbx3 that cause ulnar-mammary syndrome. Hum. Mol. Genet 10, 2403–2413 (2001). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The repression domain is essential for Tbx2/3-mediated cell senescence and tumorigenesis.

    “Other studies have revealed that such an RD is essential for Tbx2/3-mediated cell senescence and tumorigenesis.19,44”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [19] He, M., Wen, L., Campbell, C. E., Wu, J. Y. & Rao, Y. Transcription repression by Xenopus ET and its human ortholog TBX3, a gene involved in ulnar-mammary syndrome. Proc. Natl Acad. Sci. USA 96, 10212–10217 (1999). source

      The Results (page not provided) show that the conserved Tbx2/3 repression domain is required for transcriptional repression. The paper does not establish that this domain is essential for cell senescence or tumorigenesis. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [44] Jacobs, J. J. et al. Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers. Nat. Genet. 26, 291–299 (2000). source

  • May combine two claims.

    Findingown data

    Ectopic expression of wild-type Tbx3 promoted tumor metastasis in nude mice, while the Tbx3 mutant almost completely abolished the metastatic effect.

    “Consistently, ectopic expression of Tbx3 largely promoted tumor metastasis.”
    • Also stated in: § Novel motifs are essential for the promotion of HCC cell migration and metastasis by Tbx3 · plain
      “Large tumor modules were observed in all the test mice that received implanted cells that ectopically expressed wild-type Tbx3 (7 out of 7 mice, Fig. 3e), while no tumor nodules were observed in the control group (Fig. 3d).”
    • Also stated in: § Novel motifs are essential for the promotion of HCC cell migration and metastasis by Tbx3 · plain
      “Interestingly, implantation of cells that expressed the Tbx3 mutant almost completely abolished the metastatic effect (Fig. 3f).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Tbx3 mutant protein used in assays is properly folded and retains all functions other than the mutated motifs.
    • Rests on an assumption: The intrasplenic injection mouse model reflects human HCC metastasis.

  • The quote only partly states this claim.

    Findingown data

    Substitution of 604HRH606 with aspartic acid reduces RD-HDAC5 binding activity by approximately 30%.

    “In the case of 604HRH606, substitution by aspartic acid mildly reduced the binding activity of RD and HDAC5 (Fig. 6a, c, line 2).”
    • Also stated in: § Tbx3 interacts with HDAC5 through the 585LFSYPYT591 and 604HRH606 motifs · plain
      “Overall, the binding activity was reduced by ~30% in three independent experiments (Fig. 6b, d, e).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Tbx3 mutant protein used in assays is properly folded and retains all functions other than the mutated motifs.

  • May combine two claims.

    Findingown data

    Ectopic expression of wild-type Tbx3 increased HepG2 cell migration, whereas the Tbx3 mutant did not differ from the control.

    “We showed that the ectopic expression of Tbx3 was able to upregulate HepG2 cell migration, while the Tbx3 mutant did not differ from the control group (Fig. 3a–c).”
    • Also stated in: § Novel motifs are essential for the promotion of HCC cell migration and metastasis by Tbx3 · plain
      “Similar results were also obtained in Bel7404 hepatoma cells (Fig. S4A-S4C).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Tbx3 mutant protein used in assays is properly folded and retains all functions other than the mutated motifs.

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Ectopic expression of wild-type Tbx3 reduces E-cadherin protein and mRNA expression, whereas the Tbx3 mutant has no obvious effect.

    “upon ectopic expression of wild-type Tbx3, the E-cadherin protein expression level was obviously reduced, but the same effect was not observed after expression of the Tbx3 mutant form (Fig. 4c and Fig. S4D).”
    • Also stated in: § Repression motifs are required for the suppression of E-cadherin expression by Tbx3 · plain
      “we found that, in the setting of wild-type Tbx3 overexpression rather than that of the Tbx3 mutant, the E-cadherin mRNA levels were decreased in HepG2 cells (Fig. 4d).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Tbx3 mutant protein used in assays is properly folded and retains all functions other than the mutated motifs.

  • May combine two claims.

    Findingown data

    Tbx3 forms a complex with HDAC5 and together they regulate E-cadherin expression.

    “In this study, we showed that, by forming a complex with HDAC5, Tbx3 worked together with HDAC5 to regulate E-cadherin expression (Fig. 5) via forming a complex with HDAC5 (Fig. 6).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: HDACs catalyze the removal of acetyl groups from histones to condense chromatin, leading to transcriptional repression.
    • Rests on an assumption: HDACs lack a DNA-binding domain and rely on specific transcription factors to recruit and bind target promoters.

  • May combine two claims.

    Findingown data

    Simultaneous mutation of both motifs completely abolishes HDAC5 binding and RD transcriptional repression activity.

    “Consistently, the RD did not display any transcriptional repression activity when the binding activity was completely lost by simultaneous mutation of 585LFSYPYT591 and 604HRH606.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: HDACs catalyze the removal of acetyl groups from histones to condense chromatin, leading to transcriptional repression.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tbx3 may induce melanoma cell invasion by binding the E-cadherin promoter to repress its transcription.

    “Recent studies have also indicated that Tbx3 may induce melanoma cell invasion via binding the E-cadherin promoter to repress its transcription.43”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Rodriguez, M., Aladowicz, E., Lanfrancone, L. & Goding, C. R. Tbx3 represses E-cadherin expression and enhances melanoma invasiveness. Cancer Res. 68, 7872–7881 (2008). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ectopic expression of Tbx3 increases the invasiveness of melanoma cell lines.

    “Ectopic expression of Tbx3 has suggested that this protein has the ability to increase the invasiveness of melanoma cell lines.43”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Rodriguez, M., Aladowicz, E., Lanfrancone, L. & Goding, C. R. Tbx3 represses E-cadherin expression and enhances melanoma invasiveness. Cancer Res. 68, 7872–7881 (2008). source

  • May combine two claims.

    Interpretationown data

    The N-terminal deletion disrupts the 585LFSYPYT591 motif and causes complete loss of the 604HRH606 motif, explaining the loss of transcription repression activity.

    “The N-terminal deletion actually disrupts the 585LFSYPYT591 motif and causes complete loss of the 604HRH606 motif, which explains why a loss of transcription repression activity was observed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Tbx3 is a novel modulator of EMT in HCC progression and functions through regulation of E-cadherin expression.

    “which indicates that Tbx3 is a novel modulator of EMT in HCC progression and that it functions through the regulation of E-cadherin expression.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Tbx3 mutant protein used in assays is properly folded and retains all functions other than the mutated motifs.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study was approved by the Ethical Committee of Prince Wales Hospital (CUHK).

    “This study was approved by the Ethical Committee of Prince Wales Hospital (CUHK).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Sample collection procedures were approved by the Clinical Research Ethics Committee of the City University of Hong Kong.

    “All sample collection procedures were approved by the Clinical Research Ethics Committee of the City University of Hong Kong.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The novel HDAC5-interacting motifs of Tbx3 (585LFSYPYT591 and 604HRH606) are crucial for transcriptional repression of Tbx3 through interaction with HDAC5, suppression of E-cadherin expression, and promotion of HCC metastasis.

    “These results revealed that the novel HDAC5- interacting motifs of Tbx3 are crucial for the suppression of E-cadherin expression and the promotion of HCC metastasis.”
    • Also stated in: § Discussion · plain
      “The 585LFSYPYT591 and 604HRH606 motifs play a key role in transcriptional repression of Tbx3 through interaction with HDAC5, which promotes HCC metastasis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: HDACs catalyze the removal of acetyl groups from histones to condense chromatin, leading to transcriptional repression.
    • Rests on an assumption: HDACs lack a DNA-binding domain and rely on specific transcription factors to recruit and bind target promoters.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Luciferase assays were performed in triplicate and repeated three times.

    “Each assay was performed in triplicate and repeated three times.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Informed consent was obtained from each patient.

    “Informed consent was obtained from each patient.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Wound healing assays used triplicate wells and each experiment was performed three times.

    “Triplicate wells were used for each condition, and each experiment was performed three times.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Migration and invasion assays were performed as three independent experiments.

    “The migration and invasion assays were performed as three independent experiments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All constructs were confirmed by automated DNA sequencing.

    “All the constructs were confirmed by automated DNA sequencing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Stable clones were assessed by RT-PCR and western blot to confirm recombinant protein expression.

    “Stable clones were assessed by RT-PCR and western blot to confirm recombinant protein expression.”
    Quote in the paperNot a substantial claim
21 of 21

  • The paper relies on this without support.

    The Tbx3 mutant protein used in assays is properly folded and retains all functions other than the mutated motifs.

    “We simultaneously mutated the 585LFSYPYT591 and 604HRH606 motifs into glycine and performed a Transwell assay to determine their effects on cancer cell invasiveness.”

  • The paper relies on this without support.

    The mechanism by which Tbx3 participates in HCC metastasis is largely unknown.

    “However, the mechanism by which Tbx3 participates in the metastasis of hepatocellular carcinoma (HCC) remains largely unknown.”

  • The paper relies on this without support.

    The intrasplenic injection mouse model reflects human HCC metastasis.

    “HepG2 cells with stable ectopic expression of Tbx3 or Tbx3 mutant were implanted in the spleen, and tumor modules that developed in the liver were examined at the end of the experimental period.”

  • The paper relies on this without support.

    HDACs catalyze the removal of acetyl groups from histones to condense chromatin, leading to transcriptional repression.

    “Histone deacetylases (HDACs) catalyze the removal of acetyl groups from histones to condense the chromatin, which leads to transcriptional repression.”

  • The paper relies on this without support.

    HDACs lack a DNA-binding domain and rely on specific transcription factors to recruit and bind target promoters.

    “Due to the lack of a DNA-binding domain, HDACs rely on specific transcription factors to recruit and bind target promoters.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • TBX3 can interact directly with HDAC5 through two crucial motifs to facilitate cell migration by downregulating E-cadherin expression in hepatocellular carcinoma.

    “Tbx3 can interact directly with HDAC5 through two crucial motifs (585LFSYPYT591 and 604HRH606) to facilitate cell migration by downregulating E-cadherin expression in hepatocellular carcinoma 60.”

    From TBX3 shapes an immunosuppressive microenvironment and induces immunotherapy resistance (2025) · cites this paper as [60]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The N-terminal deletion has two different endpoints

    Minor

    The results describe the truncated RD as ending at residue 588, whereas the construction method says the replacement fragment ends at residue 585.

  • MT12 denotes both a single-residue and a two-motif mutation

    Minor

    MT12 is assigned to replacement of Arg605 with alanine and later to simultaneous mutation of both repression motifs.

  • The 588YPYTYMA594/604HRH606 mutant is labeled MT13 and MT14

    Minor

    The same combined mutation is identified as MT13 in one sentence and MT14 in the next.

  • The E-cadherin section misnumbers the LFSYPYT motif

    Minor

    This section twice calls the motif 85LFSYPYT591, whereas the motif is identified throughout the paper as 585LFSYPYT591.

  • The LPFHLQQ motif has inconsistent starting residue numbers

    Minor

    The same seven-residue sequence is numbered 563-569 for MT1 but 566-569 when describing MT8.

5 of 5

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Authors
Dong, L., Dong, Q., Chen, Y., Li, Y., Zhang, B., Zhou, F., Lyu, X., Chen, G. G., Lai, P., Kung, H.-F., & He, M.-L.
Affiliations
  • City University of Hong Kong (HK)
  • Southern Medical University (CN)
  • Chinese University of Hong Kong (HK)
  • Army Medical University (CN)
Corresponding author
He, Ming-Liang
ORCID
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2018-08-24
Volume
3
Issue
1
Pages
22-22
ISSN
2059-3635 (ISSN-L)
DOI
10.1038/s41392-018-0025-6
PMC
PMC6107554
OpenAlex
W2888378005
Cited by
36
References
60
Citations by year
2026: 2 · 2025: 4 · 2023: 7 · 2022: 4 · 2021: 7 · 2020: 6 · 2019: 5 · 2018: 1
FWCI
1.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • CityU Scholars (submittedVersion, cc-by)
Funders
  • City University of Hong Kong (9680149)
  • National Natural Science Foundation of China (81471964, 81671995, 81702510)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Keywords
TBX3, HDAC5, hepatocellular carcinoma, metastasis, E-cadherin, transcriptional repression, protein interaction motifs, cell migration, histone deacetylase inhibitors, transcriptional repressor

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