A CDCA2–MYC positive feedback loop controls cancer cells survival

Abstract

Cellular myelocytomatosis oncogene (MYC) transcription factors are encoded by a family of genes that include the prototype member MYC, MYCN and MYCL, and most human cancers display expression alterations of MYC genes. MYC is regulated at multiple levels, and its stability and activity are modulated by protein phosphorylation. Although there is a reasonable knowledge of the kinases required for MYC modifications, the counteracting phosphatases have been understudied. Here, we have investigated the role of the chromatin-associated protein phosphatase 1 (PP1) regulatory subunit CDCA2, also known as Repo-Man, in the regulation of MYC proteins in cancer cells. Using RNA interference and degron-mediated degradation of CDCA2, we have demonstrated that the PP1 subunit is required for cMYC and MYCN stabilization and viability of triple-negative breast cancer, neuroblastoma and colon cancer cells. Proximity ligation assays indicate that both cMYC and MYCN are in close proximity to CDCA2 in vivo. Furthermore, we have shown that CDC2A is a bona fide MYC target gene in cancer cells, revealing a reciprocal regulatory loop that could be exploited for therapeutic purposes.