Dataset Information

Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer.

ABSTRACT: Altered RNA expression of repetitive sequences and retrotransposition are frequently seen in colorectal cancer, implicating a functional importance of repeat activity in cancer progression. We show the nucleoside reverse transcriptase inhibitor 3TC targets activities of these repeat elements in colorectal cancer preclinical models with a preferential effect in p53-mutant cell lines linked with direct binding of p53 to repeat elements. We translate these findings to a human phase II trial of single-agent 3TC treatment in metastatic colorectal cancer with demonstration of clinical benefit in 9 of 32 patients. Analysis of 3TC effects on colorectal cancer tumorspheres demonstrates accumulation of immunogenic RNA:DNA hybrids linked with induction of interferon response genes and DNA damage response. Epigenetic and DNA-damaging agents induce repeat RNAs and have enhanced cytotoxicity with 3TC. These findings identify a vulnerability in colorectal cancer by targeting the viral mimicry of repeat elements.

Significance

Colorectal cancers express abundant repeat elements that have a viral-like life cycle that can be therapeutically targeted with nucleoside reverse transcriptase inhibitors (NRTI) commonly used for viral diseases. NRTIs induce DNA damage and interferon response that provide a new anticancer therapeutic strategy. This article is highlighted in the In This Issue feature, p. 1397.

SUBMITTER: Rajurkar M

PROVIDER: S-EPMC9167735 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer.

Rajurkar Mihir M Parikh Aparna R AR Solovyov Alexander A You Eunae E Kulkarni Anupriya S AS Chu Chong C Xu Katherine H KH Jaicks Christopher C Taylor Martin S MS Wu Connie C Alexander Katherine A KA Good Charly R CR Szabolcs Annamaria A Gerstberger Stefanie S Tran Antuan V AV Xu Nova N Ebright Richard Y RY Van Seventer Emily E EE Vo Kevin D KD Tai Eric C EC Lu Chenyue C Joseph-Chazan Jasmin J Raabe Michael J MJ Nieman Linda T LT Desai Niyati N Arora Kshitij S KS Ligorio Matteo M Thapar Vishal V Cohen Limor L Garden Padric M PM Senussi Yasmeen Y Zheng Hui H Allen Jill N JN Blaszkowsky Lawrence S LS Clark Jeffrey W JW Goyal Lipika L Wo Jennifer Y JY Ryan David P DP Corcoran Ryan B RB Deshpande Vikram V Rivera Miguel N MN Aryee Martin J MJ Hong Theodore S TS Berger Shelley L SL Walt David R DR Burns Kathleen H KH Park Peter J PJ Greenbaum Benjamin D BD Ting David T DT

Cancer discovery 20220601 6

Altered RNA expression of repetitive sequences and retrotransposition are frequently seen in colorectal cancer, implicating a functional importance of repeat activity in cancer progression. We show the nucleoside reverse transcriptase inhibitor 3TC targets activities of these repeat elements in colorectal cancer preclinical models with a preferential effect in p53-mutant cell lines linked with direct binding of p53 to repeat elements. We translate these findings to a human phase II trial of sing ...[more]

PMID: 35320348

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Project description:Transposable elements (TEs) are mobile genomic sequences that encompass roughly 50% of the human genome. Class 1 TEs, or "retrotransposons," mobilize through the production of an RNA intermediate that is then reverse transcribed to form complementary DNA (cDNA) molecules capable of genomic reinsertion. While TEs are traditionally silenced to maintain genomic integrity, the recognition of immunostimulatory cues, such as those provided by microorganisms, drastically alters host transcription to induce the differential expression of TEs. Emerging evidence demonstrates that the inducible production of TE cDNA is not an inert phenomenon but instead has been coopted by host immunity to facilitate cross talk between host and constituents of the microbiota by agonizing intrinsic antiviral receptors. Here, we demonstrate that immunostimulation of toll-like receptor 4 (TLR4) with lipopolysaccharide (LPS) and TLR5 with bacterial flagella (FLA) alters the expression of retrotransposons, such as human endogenous retroviruses (HERVs) and long interspersed nuclear elements (LINEs). Next, we demonstrate that reverse transcriptase inhibitor (RTi) delivery ameliorates the acute production of the proinflammatory cytokine "tumor necrosis factor alpha" (TNF-α) in response to FLA in a monocytic cell line (THP-1). Collectively, our findings demonstrate that TLR5-mediated cross talk between the host and microbiota is partially dependent on the reverse transcription (RT) of retrotransposons. IMPORTANCE The microbiota is a potent reservoir of immunostimulatory and immunosuppressive motifs that fundamentally shape host immunity. Despite broad associations between microbial composition and host immunity, the mechanisms underlying host microbiota-induced immunoregulation remain poorly defined. Here, we demonstrate a novel mechanism by which motifs overabundant during dysbiotic conditions influence host immunity through the upregulation of endogenous RT to produce motifs that agonize antiviral receptors.

Dataset Information

Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer.

Significance

Publications

Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer.

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