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DNA hypomethylation promotes transposable element expression and activation of immune signaling in renal cell cancer
Aguirre A. de Cubas, … , John Karijolich, W. Kimryn Rathmell
Aguirre A. de Cubas, … , John Karijolich, W. Kimryn Rathmell
Published June 4, 2020
Citation Information: JCI Insight. 2020;5(11):e137569. https://doi.org/10.1172/jci.insight.137569.
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Research Article Immunology Oncology

DNA hypomethylation promotes transposable element expression and activation of immune signaling in renal cell cancer

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Abstract

Recently, we reported that expression of endogenous retroviruses (ERVs) is associated with response to immune checkpoint blockade (ICB) in renal cell carcinoma (RCC). We show that decitabine, a DNA hypomethylating agent, activates transposable element (TE) expression (LINE1 and ERVs ERV3-2 and ERV4700) and antiviral signaling to potentially enhance response to ICB in kidney cancer cell lines and primary cells. KO of RIGI and MDA5 dsRNA sensors attenuated activation of antiviral signaling associated with DNA hypomethylation, and RIGI and MDA5 IPs showed increased ERV binding with decitabine treatment. Bioinformatic analyses showed the decitabine-induced signature could be associated with increased immune infiltration and response to ICB. Cytokine secretion induced by decitabine could modestly improve T cell activation and robustly enhanced T cell migration. In a small retrospective cohort of metastatic clear cell RCC (ccRCC) patients treated with anti-PD1/PDL1 blockade, activation of some antiviral genes was significantly higher in responders. Thus, we identified a potential strategy to induce TE expression through inhibition of DNA methylation in modulating T cell action via regulation of the innate antiviral pathway.

Authors

Aguirre A. de Cubas, William Dunker, Andrew Zaninovich, Rachel A. Hongo, Anuj Bhatia, Anshuman Panda, Kathryn E. Beckermann, Gyan Bhanot, Shridar Ganesan, John Karijolich, W. Kimryn Rathmell

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Figure 1

Decitabine induces DNA hypomethylation in ccRCC cell lines.

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Decitabine induces DNA hypomethylation in ccRCC cell lines.
Kidney cell ...
Kidney cell lines were treated with the indicated doses of decitabine for 3 consecutive days and assayed on day 5. (A) Decitabine dose-response curve for viability in panel of kidney cell lines (A498, HKC, RPTec, UMRC2, and 786-0). All data are mean ± SD (n = 3). (B and C) DNMT1 protein levels were assessed in HKC (B) and 786-0 (C) by immunoblot analysis. β-Actin was included as a loading control. (D) DNA methylation levels were assayed in 786-0 cells treated with decitabine. Violin plot showing distribution of DNA methylation patterns for the 50,000 most variably methylated probes. Black dot and line at violin center indicate mean ± SD. Data represent the mean of duplicate samples.

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