Summary
This research reveals how our body’s response to DNA damage, which normally helps prevent tumors, can sometimes backfire. This response can accidentally turn on certain genes that increase the risk of cancer. Specifically, it can reactivate a gene called OCT4, usually active in early development, which is supposed to be switched off in adult cells. This reactivation is partly due to changes in how DNA is packaged and controlled, which are triggered by DNA damage.
Interestingly, the full activation of OCT4 also depends on other cancer-related factors, like certain oncogenes, which are genes that, when mutated or expressed at high levels, help turn a normal cell into a cancer cell. Our studies using advanced techniques in mice and human cancer cells show that when OCT4 is reactivated, it makes cancer cells resistant to chemotherapy and more likely to cause the cancer to return.
However, we’ve found that by turning off OCT4, we can reduce this resistance and delay the return of the cancer. This discovery is crucial because it points to new ways to treat cancer, potentially leading to therapies that prevent cancer cells from resisting treatment and relapsing. This could make a significant difference in the success of cancer treatments.
Abstract
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.
