Dataset Information

SETDB1 Restrains Endogenous Retrovirus Expression and Antitumor Immunity during Radiotherapy.

ABSTRACT: The type I interferon response plays a pivotal role in promoting antitumor immune activity in response to radiotherapy. The identification of approaches to boost the radiation-induced type I interferon response could help improve the efficacy of radiotherapy. Here we show that the histone methyltransferase SETDB1 is a potent suppressor of radiation-induced endogenous retrovirus expression. SETDB1 inhibition significantly enhanced the efficacy of radiotherapy by promoting radiation-induced viral mimicry to upregulate type I interferons. SETDB1 expression correlated with radiotherapy efficacy in human non-small cell carcinoma and melanoma patients. In a murine tumor model, genetic deletion of Setdb1 significantly enhanced radiotherapy efficacy, and Setdb1-deficient tumors had enhanced intratumoral lymphocyte infiltration, an observation confirmed in human cancer samples. Setdb1 deficiency led to increased basal and radiation-induced endogenous retrovirus (ERV) expression, enhanced MDA5/MAVS signaling, and upregulated type I interferons, which were essential for SETDB1 deficiency-induced radiosensitization. Taken together, these data suggest that inhibition of SETDB1 is a promising approach to enhance cancer radiotherapy efficacy by promoting radiation-induced viral mimicry and antitumor immunity through ERV induction.

Significance

The identification of the SETDB1-mediated suppression of radiotherapy-induced viral mimicry reveals SETDB1 inhibition as a potential approach to sensitize tumors to radiotherapy by enhancing the type I interferon response.

SUBMITTER: Pan D

PROVIDER: S-EPMC9357127 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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SETDB1 Restrains Endogenous Retrovirus Expression and Antitumor Immunity during Radiotherapy.

Pan Dong D Bao Xuhui X Hu Mengjie M Jiao Meng M Li Fang F Li Chuan-Yuan CY

Cancer research 20220801 15

The type I interferon response plays a pivotal role in promoting antitumor immune activity in response to radiotherapy. The identification of approaches to boost the radiation-induced type I interferon response could help improve the efficacy of radiotherapy. Here we show that the histone methyltransferase SETDB1 is a potent suppressor of radiation-induced endogenous retrovirus expression. SETDB1 inhibition significantly enhanced the efficacy of radiotherapy by promoting radiation-induced viral ...[more]

PMID: 35648422

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Project description:Background & aimsThe 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.MethodsThe 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.ResultsTCGA 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.ConclusionsThe 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 implicationsAn 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.

Dataset Information

SETDB1 Restrains Endogenous Retrovirus Expression and Antitumor Immunity during Radiotherapy.

Significance

Publications

SETDB1 Restrains Endogenous Retrovirus Expression and Antitumor Immunity during Radiotherapy.

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