DNA Damage Signaling-Induced Cancer Cell Reprogramming as a Driver of Tumor Relapse

Accumulating evidence supports the role of the DNA damage response (DDR) in the negative regulation of tumorigenesis. Here, we found that DDR signaling poises a series of epigenetic events, resulting in activation of pro-tumorigenic genes but can go as far as reactivation of the pluripotency gene OCT4. Loss of DNA methylation appears to be a key initiating event in DDR-dependent OCT4 locus reactivation although full reactivation required the presence of a driving oncogene, such as Myc and macroH2A downregulation. Using genetic-lineage-tracing experiments and an in situ labeling approach, we show that DDR-induced epigenetic reactivation of OCT4 regulates the resistance to chemotherapy and contributes to tumor relapse both in mouse and primary human cancers. In turn, deletion of OCT4 reverses chemoresistance and delays the relapse. Here, we uncovered an unexpected tumor-promoting role of DDR in cancer cell reprogramming, providing novel therapeutic entry points for cancer intervention strategies. [Display omitted] •DDR signaling induces DNA demethylation at defined loci, including OCT4 and NANOG•macroH2A counterbalances a DDR-signaling-induced activation of OCT4•MYC and SOX2 cooperate with DDR signaling to activate OCT4 transcription•OCT4 reactivation contributes to cancer drug resistance and tumor relapse The work by Filipponi et al. supports a model in which many, if not all, cancer cells independent of hierarchical organization can be challenged by DNA damage-induced signaling to undergo a series of epigenetic reprograming events, including reactivation of OCT4, ultimately contributing to development of drug resistance and tumor relapse.