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Published on: November 2, 2013
Identification and clinical implications of endogenous retrovirus elements suppressed by SETDB1 in hepatocellular
Yosuke Igarashi1,2, Yoshimitsu Akiyama1, Shu Shimada1
1Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
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.
Insights
SETDB1 suppresses human endogenous retroviruses (HERVs) in liver cancer. Low HERV expression indicates poor prognosis, while activating these HERVs may offer a new HCC therapy.
Area of Science:
- Epigenetics and Cancer Biology
- Virology and Immunology
Background:
- Inhibition of epigenetic regulators can activate endogenous retroviruses (ERVs), potentially triggering a viral mimicry response in cancer cells.
- Aberrant ERV expression is observed in hepatocellular carcinoma (HCC), but their regulation by histone modifications and clinical significance are not fully understood.
- Specific human endogenous retrovirus (HERV) elements epigenetically suppressed by SETDB1 in HCC were identified.
Purpose of the Study:
- To investigate the role of SETDB1 in regulating HERV expression in hepatocellular carcinoma (HCC).
- To determine the clinical significance of SETDB1-regulated HERVs as prognostic markers in HCC.
- To explore the therapeutic potential of activating SETDB1-regulated HERVs in HCC.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA) dataset to identify HERV elements based on SETDB1 expression levels.
- SETDB1 knockdown (KD) in mouse and human HCC cells to assess biological effects and HERV expression changes.
- In vitro and in vivo experiments to evaluate tumor growth, immune cell infiltration, and gene expression patterns.
Main Results:
- An inverse correlation between SETDB1 and retroelements was found in human HCC (R = -0.723, p = 2.297 × 10⁻⁴⁰).
- Four specific HERV elements were identified in SETDB1-high HCC cases; low expression correlated with poor prognosis.
- SETDB1 depletion in HCC cells led to increased HERV expression, decreased H3K9me3, elevated interferon-stimulated genes indicating viral mimicry, and impaired tumor growth with increased CD8+ T-cell infiltration in vivo.
Conclusions:
- The suppression of four HERV elements by SETDB1 serves as a prognostic marker in HCC.
- SETDB1-regulated HERVs represent potential therapeutic targets for HCC.
- Activation of these HERVs may induce a viral mimicry response, offering a promising therapeutic strategy.
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