Beyond DNA Repair: DNA-PKcs in Tumor Metastasis, Metabolism and Immunity

SIMPLE SUMMARY: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has recently attracted increasing attention due to the emerging novel functions in cancer. However, several fundamental questions, such as the underlying molecular basis for DNA-PKcs pleiotropy and biomarkers for DNA-PKcs inhibitor sensitivity, remain to be addressed. In this review, we elaborate an updated summary of the most recent progress in DNA-PKcs, with particular emphasis on the mechanisms of DNA-PKcs multifaceted roles in malignancy and potential stratification approaches towards DNA-PKcs-based precision cancer therapy. ABSTRACT: The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key component of the DNA-PK complex that has a well-characterized function in the non-homologous end-joining repair of DNA double-strand breaks. Since its identification, a large body of evidence has demonstrated that DNA-PKcs is frequently overexpressed in cancer, plays a critical role in tumor development and progression, and is associated with poor prognosis of cancer patients. Intriguingly, recent studies have suggested novel functions beyond the canonical role of DNA-PKcs, which has transformed the paradigm of DNA-PKcs in tumorigenesis and has reinvigorated the interest to target DNA-PKcs for cancer treatment. In this review, we update recent advances in DNA-PKcs, in particular the emerging roles in tumor metastasis, metabolic dysregulation, and immune escape. We further discuss the possible molecular basis that underpins the pleiotropism of DNA-PKcs in cancer. Finally, we outline the biomarkers that may predict the therapeutic response to DNA-PKcs inhibitor therapy. Understanding the functional repertoire of DNA-PKcs will provide mechanistic insights of DNA-PKcs in malignancy and, more importantly, may revolutionize the design and utility of DNA-PKcs-based precision cancer therapy.