Paper Title
THE E3 LIGASE RINES IS A BROAD TUMOR SUPPRESSOR RESTRAINING CARCINOMA CELL STEMNESS

Abstract
Deregulation of protein modifications, to the stability and functional activation of regulatory proteins such as oncoproteins STAT3 and MYC, is involved in multiple tumorigeneses. Roles in cancer stemness and underlying mechanisms of the E3 ubiquitin ligase RINES in carcinogenesis remains to be elucidated. Here, we identified the tumor-specific promoter CpG methylation of RINES in some common cancers - esophageal, nasopharyngeal, colorectal and breast carcinomas, which is associated with patient poor survival. We also found that RINES is a bona fide tumor suppressor that inhibits tumor cell growth in vivo and in vitro. Mechanistically, RINES as an E3 ubiquitin ligase physically interacts with STAT3 and MYC, facilitating their protein degradation. Degradation of STAT3 and MYC mediated by RINES through its RING domain is required for cancer cell stemness properties. Moreover, knockdown of RINES expression resulted in decreased ubiquitination of STAT3 and MYC proteins and increased protein stability, further promoting the stemness features of tumor cells and tumorigenesis. Thus, our study identified RINES as a broad tumor suppressor that directly regulates STAT3 and MYC stability and cell stemness characteristics. Its promoter CpG methylation could serve as a potential biomarker for common cancers.