CoChat
Sign Up
Cited by 10Epigenetics and DNA MethylationCancer-related molecular mechanisms researchChromosomal and Genetic Variations

Identification and clinical implications of endogenous retrovirus elements suppressed by SETDB1 in hepatocellular carcinoma

Open access
Igarashi, Yosuke, Akiyama, Yoshimitsu, Shimada, Shu, Watanabe, Shuichi, Hatano, Megumi, Kodera, Keita, Okazaki, Kohei, Tanji, Yoshiaki +14 more·2025·JHEP Reports
DOI 10.1016/j.jhepr.2024.101307PMC PMC11889587
Open this paper in CoChat — free account

Abstract

Background & Aims The inhibition of epigenetic regulators activates endogenous retrovirus (ERV) expression, which can stimulate a viral mimicry response in cancer cells. ERV elements are aberrantly expressed in hepatocellular carcinoma (HCC); however, the expression of ERVs regulated by histone modifications and their clinical significance in HCC remain unclear. Here, we identified specific human endogenous retrovirus (HERV) elements epigenetically suppressed by the histone methyltransferase SETDB1 in HCC. Methods The Cancer Genome Atlas (TCGA) dataset was analyzed to identify HERV elements based on SETDB1 expression levels. SETDB1 knockdown (KD) was performed in mouse and human HCC cells to investigate the resulting biological effects and changes in HERV expression, both in vitro and in vivo . Results TCGA analysis revealed an inverse correlation between SETDB1 and retroelements in human HCC (R = -0.723, p = 2.297 × 10 -40 ), identifying four specific HERV elements in SETDB1 -high expressing HCC cases. Low expression of these four HERVs was associated with poor prognosis, and their combined expression provided additional prognostic insight ( p <0.001). Increased expression of the four HERV elements and decreased H3K9me3 levels at these regions were detected in human HCC cells with SETDB1 -KD. In murine HCC cells, Setdb1 -KD impaired in vivo tumor growth with increasing CD8-positive T-cell infiltration. Moreover, the interferon α response pathway and multiple ERV elements were activated in mouse HCC cells with Setdb1 -KD. The expression of interferon-stimulated genes, as indicators of a viral mimicry response, was elevated in both murine and human SETDB1 -KD HCC cells. Conclusions The suppression of four novel HERV elements by SETDB1 serves as a prognostic marker in HCC. Activation of these SETDB1-regulated HERVs could represent a promising therapeutic strategy for HCC. Impact and implications: An inverse relationship between retroelements including human endogenous retrovirus (HERV) elements and SETDB1 expression was observed in human hepatocellular carcinoma (HCC) by The Cancer Genome Atlas data analysis. We identified four HERV elements downregulated by SETDB1-dependent H3K9me3 in HCC cells, with low expression levels of these HERV elements correlating with poor prognosis in patients with HCC. SETDB1 depletion resulted in upregulation of various interferon-stimulated genes associated with viral mimicry in HCC cells. These findings suggest that the four SETDB1-regulated HERVs could serve as prognostic markers and potential therapeutic targets for HCC.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.jhepr.2024.101307

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • Knockdown of SETDB1 in HCC cells led to the transcriptional derepression of two HERVE-int elements through loss of H3K9me3.

    “a recent study demonstrated that knockdown of SETDB1, the H3K9 methyltransferase, in HCC cells led to the transcriptional derepression of two HERVE-int elements through loss of H3K9me3”

    From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [63]

    The Results section (page not provided) reports that SETDB1 knockdown increased expression of four HERV elements in HCC cells and reduced H3K9me3 at their regions. It does not identify two HERVE-int elements: the four tested elements include one HERVE-int element, on chromosome 5. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

Self-check

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

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 46

  1. [1]Sung H. Ferlay J. Siegel R.L. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 71 2021 209 249 33538338
  2. [3]Jansz N. Faulkner G.J. Endogenous retroviruses in the origins and treatment of cancer Genome Biol 22 2021 147 33971937 PMC8108463
  3. [4]Vargiu L. Rodriguez-Tome P. Sperber G.O. Classification and characterization of human endogenous retroviruses; mosaic forms are common Retrovirology 13 2016 7 26800882 PMC4724089
  4. [5]Srinivasachar Badarinarayan S. Shcherbakova I. Langer S. HIV-1 infection activates endogenous retroviral promoters regulating antiviral gene expression Nucleic Acids Res 48 2020 10890 10908 33021676 PMC7641743
  5. [7]Nexo B.A. Villesen P. Nissen K.K. Are human endogenous retroviruses triggers of autoimmune diseases? Unveiling associations of three diseases and viral loci Immunol Res 64 2016 55 63 26091722 PMC4726719
  6. [8]Reddam A. Bollati V. Wu H. Air pollution and human endogenous retrovirus methylation in the school inner-city asthma intervention study Toxicol Sci 193 2023 166 174 37042721 PMC10230279
  7. [9]Liu T. Xing Y. Fan X. Fasting and overfeeding affect the expression of the immunity- or inflammation-related genes in the liver of poultry via endogenous retrovirus Poult Sci 100 2021 973 981 33518151 PMC7858184
  8. [10]Liu C. Liu L. Wang X. HBV X Protein induces overexpression of HERV-W env through NF-kappaB in HepG2 cells Virus Genes 53 2017 797 806 28639221
  9. [11]Ma W. Hong Z. Liu H. Human endogenous retroviruses-K (HML-2) expression is correlated with prognosis and progress of hepatocellular carcinoma Biomed Res Int 2016 8201642 PMC5192314 28070518
  10. [12]Chang Y.S. Hsu M.H. Chung C.C. Comprehensive analysis and drug modulation of human endogenous retrovirus in hepatocellular carcinomas Cancers (Basel) 15 2023 PMC10377948 37509325
  11. [13]Chen R. Ishak C.A. De Carvalho D.D. Endogenous retroelements and the viral mimicry response in cancer therapy and cellular homeostasis Cancer Discov 11 2021 2707 2725 34649957
  12. [15]Lazaro-Camp V.J. Salari K. Meng X. SETDB1 in cancer: overexpression and its therapeutic implications Am J Cancer Res 11 2021 1803 1827 34094655 PMC8167684
  13. [16]Wong C.M. Wei L. Law C.T. Up-regulation of histone methyltransferase SETDB1 by multiple mechanisms in hepatocellular carcinoma promotes cancer metastasis Hepatology 63 2016 474 487 26481868
  14. [17]Xiang J. Chen X. Chen M. Increased expression of SETDB1 predicts poor prognosis in multiple myeloma Biomed Res Int 2022 3307873 PMC8967582 35372573
  15. [18]Pan D. Bao X. Hu M. SETDB1 restrains endogenous retrovirus expression and antitumor immunity during radiotherapy Cancer Res 82 2022 2748 2760 35648422 PMC9357127
  16. [19]Hu H. Khodadadi-Jamayran A. Dolgalev I. Targeting the Atf7ip-Setdb1 complex augments antitumor immunity by boosting tumor immunogenicity Cancer Immunol Res 9 2021 1298 1315 34462284 PMC9414288
  17. [20]Cuellar T.L. Herzner A.M. Zhang X. Silencing of retrotransposons by SETDB1 inhibits the interferon response in acute myeloid leukemia J Cell Biol 216 2017 3535 3549 28887438 PMC5674883
  18. [21]Chan F.F. Yuen V.W. Shen J. Inhibition of CAF-1 histone chaperone complex triggers cytosolic DNA and dsRNA sensing pathways and induces intrinsic immunity of hepatocellular carcinoma Hepatology 80 2024 295 311 38051950
  19. [22]Shimada S. Mogushi K. Akiyama Y. Comprehensive molecular and immunological characterization of hepatocellular carcinoma EBioMedicine 40 2019 457 470 30598371 PMC6412165
  20. [23]Fei Q. Shang K. Zhang J. Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53 Nat Commun 6 2015 8651 26471002 PMC5426523
  21. [24]Kato M. Takemoto K. Shinkai Y. A somatic role for the histone methyltransferase Setdb1 in endogenous retrovirus silencing Nat Commun 9 2018 1683 29703894 PMC5923290
  22. [25]Hosseini A. Lindholm H.T. Chen R. Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer Cell Rep 43 2024 113684 PMC11724374 38261511
  23. [26]Schoggins J.W. Rice C.M. Interferon-stimulated genes and their antiviral effector functions Curr Opin Virol 1 2011 519 525 22328912 PMC3274382
  24. [27]Ryu T.Y. Kim K. Kim S.K. SETDB1 regulates SMAD7 expression for breast cancer metastasis BMB Rep 52 2019 139 144 30545440 PMC6443319
  25. [28]Palakurthy R.K. Wajapeyee N. Santra M.K. Epigenetic silencing of the RASSF1A tumor suppressor gene through HOXB3-mediated induction of DNMT3B expression Mol Cell 36 2009 219 230 19854132 PMC2776651
  26. [29]Cao N. Yu Y. Zhu H. SETDB1 promotes the progression of colorectal cancer via epigenetically silencing p21 expression Cell Death Dis 11 2020 351 32393761 PMC7214465
  27. [30]Han Y. Zhang X. Guan M. RASSF4 inhibits cell proliferation and increases drug sensitivity in colorectal cancer through YAP/Bcl-2 pathway J Cell Mol Med 26 2022 3538 3547 35611809 PMC9189339
  28. [31]Huang X.Y. Shi G.M. Devbhandari R.P. Low level of low-density lipoprotein receptor-related protein 1 predicts an unfavorable prognosis of hepatocellular carcinoma after curative resection PLoS One 7 2012 e32775 PMC3299691 22427881
  29. [32]Deng L. Niu G.M. Ren J. Identification of ATP8B1 as a tumor suppressor gene for colorectal cancer and its involvement in phospholipid homeostasis Biomed Res Int 2020 2015648 PMC7542516 33062669
  30. [33]Liot S. Aubert A. Hervieu V. Loss of tenascin-X expression during tumor progression: a new pan-cancer marker Matrix Biol Plus 6–7 2020 100021 PMC7852205 33543019
  31. [34]Mei J. Hu K. Peng X. Decreased expression of SLC16A12 mRNA predicts poor prognosis of patients with clear cell renal cell carcinoma Medicine (Baltimore) 98 2019 e16624 PMC6708703 31348313
  32. [35]Liu Y. Hu L. Wu Z. Loss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons Nat Commun 14 2023 4225 37454216 PMC10349869
  33. [36]Liu M. Thomas S.L. DeWitt A.K. Dual inhibition of DNA and histone methyltransferases increases viral mimicry in ovarian cancer cells Cancer Res 78 2018 5754 5766 30185548 PMC6191339
  34. [37]Fresquet V. Garcia-Barchino M.J. Larrayoz M. Endogenous retroelement activation by epigenetic therapy reverses the Warburg effect and elicits mitochondrial-mediated cancer cell death Cancer Discov 11 2021 1268 1285 33355179
  35. [38]Leung D.C. Lorincz M.C. Silencing of endogenous retroviruses: when and why do histone marks predominate? Trends Biochem Sci 37 2012 127 133 22178137
  36. [39]Chiappinelli K.B. Strissel P.L. Desrichard A. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses Cell 162 2015 974 986 26317466 PMC4556003
  37. [40]Zhang M. Liang J.Q. Zheng S. Expressional activation and functional roles of human endogenous retroviruses in cancers Rev Med Virol 29 2019 e2025 PMC6590502 30614117
  38. [41]Fasching L. Kapopoulou A. Sachdeva R. TRIM28 represses transcription of endogenous retroviruses in neural progenitor cells Cell Rep 10 2015 20 28 25543143 PMC4434221
  39. [42]Jin L. He J. Feng H. Transposable elements activation triggers necroptosis in mouse embryonic stem cells Cell Death Dis 14 2023 184 36882393 PMC9992707
  40. [43]Raviram R. Rocha P.P. Luo V.M. Analysis of 3D genomic interactions identifies candidate host genes that transposable elements potentially regulate Genome Biol 19 2018 216 30541598 PMC6292174
  41. [44]Balaj L. Lessard R. Dai L. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences Nat Commun 2 2011 180 21285958 PMC3040683
  42. [45]Wang-Johanning F. Li M. Esteva F.J. Human endogenous retrovirus type K antibodies and mRNA as serum biomarkers of early-stage breast cancer Int J Cancer 134 2014 587 595 23873154 PMC4191919
  43. [46]Li M. Radvanyi L. Yin B. Downregulation of human endogenous retrovirus type K (HERV-K) viral env RNA in pancreatic cancer cells decreases cell proliferation and tumor growth Clin Cancer Res 23 2017 5892 5911 28679769 PMC5777511
  44. [47]Li H. Rauch T. Chen Z.X. The histone methyltransferase SETDB1 and the DNA methyltransferase DNMT3A interact directly and localize to promoters silenced in cancer cells J Biol Chem 281 2006 19489 19500 16682412
  45. [48]Guo Y. Mao X. Xiong L. Structure-guided discovery of a potent and selective cell-active inhibitor of SETDB1 tudor domain Angew Chem Int Ed Engl 60 2021 8760 8765 33511756
  46. [49]Federico A. Steinfass T. Larribere L. Mithramycin A and mithralog EC-8042 inhibit SETDB1 expression and its oncogenic activity in malignant melanoma Mol Ther Oncolytics 18 2020 83 99 32637583 PMC7327877

Cited by

Sorted by citations

Authors
Igarashi, Y., Akiyama, Y., Shimada, S., Watanabe, S., Hatano, M., Kodera, K., Okazaki, K., Tanji, Y., Tsukihara, S., Taniai, T., Nara, A., Yamane, M., Kamachi, A., Umemura, K., Yasukawa, K., Ono, H., Akahoshi, K., Tanabe, M., Haruki, K., Furukawa, K., Ikegami, T., & Tanaka, S.
Affiliations
  • Jikei University School of Medicine (JP)
  • Tokyo Medical and Dental University (JP)
Corresponding author
  • Akiyama, Yoshimitsu
  • Tanaka, Shinji
ORCID
Venue
JHEP Reports
Publisher
Elsevier BV
Published
2025-03
Volume
7
Issue
3
Pages
101307
ISSN
2589-5559 (ISSN-L)
DOI
10.1016/j.jhepr.2024.101307
PMC
PMC11889587
OpenAlex
W4405528039
Cited by
10
References
3
Citations by year
2026: 5 · 2025: 5
FWCI
1.36
Type
journal article
Language
en
Open access
Licence
Locations
  • JHEP Reports (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Japan Agency for Medical Research and Development (JP23fk0210090, JP24fk0210102, JP24fk0210136, JP24fk0210106)
  • Princess Takamatsu Cancer Research Fund (JP24fk0210149, JP19cm0106540)
  • Japan Society for the Promotion of Science (23K27670, 20K21627, 23H02979, JP24fk0210149, 19H01055, 24K02320)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
Keywords
hepatocellular carcinoma, endogenous retroviruses, SETDB1, H3K9me3, histone methyltransferase, epigenetic regulation, interferon-alpha response, interferon-stimulated genes, prognostic factors, tumor growth, therapeutic target

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review