The central precocious puberty-associated gene MKRN3 is a tumor suppressor regulating CSDE1 ubiquitination in ovarian cancer

Earlier age at menarche has long been known to be associated with an increased risk of ovarian cancer (OC). However, the underlying mechanisms are not completely understood. Here, we report a paternally inherited imprinted gene, MKRN3, that is associated with central precocious puberty (CPP) and that plays a tumor suppressive role in OC. We found that genomic MKRN3 mutations are significantly more common in OC patients. Genomic mutations in MKRN3 and low MKRN3 expression levels are correlated with poor patient survival. The restoration of MKRN3 in MKRN3-inactivated OC cells significantly suppresses tumor growth and proliferation in vitro and in vivo. Ovary-specific knockout of endogenous MKRN3 accelerates P53 inactivation-induced tumorigenesis in mice. Mechanistically, CSDE1 was identified as a major substrate for MKRN3 in OC via mass spectrometry-based proteomics screens. MKRN3 regulates OC cell proliferation through proteolytic ubiquitination of CSDE1. Our comprehensive data reveal that the CPP-associated gene MKRN3 is a tumor suppressor in human OC. We propose that germline mutations in the MKRN3 gene might partially explain the association between precocious puberty and the risk of OC.