Autophagy is an evolutionarily conserved catabolic process, which plays a vital role in removing misfolded proteins and clearing damaged organelles to maintain internal environment homeostasis. Here, we uncovered the checkpoint kinase 2 (CHK2)-FOXK (FOXK1 and FOXK2) axis playing an important role in DNA damage-mediated autophagy at the transcriptional regulation layer. Mechanistically, following DNA damage, CHK2 phosphorylates FOXK and creates a 14-3-3 binding site, which, in turn, traps FOXK proteins in the cytoplasm. Because FOXK functions as the transcription suppressor of ATGs, DNA damage-mediated FOXKs' cytoplasmic trapping induces autophagy. In addition, we found that a cancer-derived FOXK mutation induces FOXK hyperphosphorylation and enhances autophagy, resulting in chemoresistance. Cotreatment with cisplatin and chloroquine overcomes the chemoresistance caused by FOXK mutation. Overall, our study highlights a mechanism whereby DNA damage triggers autophagy by increasing autophagy genes via CHK2-FOXK-mediated transcriptional control, and misregulation of this pathway contributes to chemoresistance.

Extrachromosomal circular DNA was recently found to be particularly abundant in multiple human cancer cells, although its frequency varies among different tumor types. Elevated levels of extrachromosomal circular DNA have been considered an effective biomarker of cancer pathogenesis. Multiple reports have demonstrated that the amplification of oncogenes and therapeutic resistance genes located on extrachromosomal DNA is a frequent event that drives intratumoral genetic heterogeneity and provides a potential evolutionary advantage. This review highlights the current understanding of the extrachromosomal circular DNA present in the tissues and circulation of patients with advanced cancers and provides a detailed discussion of their substantial roles in tumor regulation. Confirming the presence of cancer-related extrachromosomal circular DNA would provide a putative testing strategy for the precision diagnosis and treatment of human malignancies in clinical practice.

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