Loss of E3 Ubiquitin Ligase RINES via CpG Methylation Relieves Suppression of STAT3 and MYC, Facilitating Multiple Tumorigeneses

ABSTRACT Dysregulated protein modifications alter the stability and activation status of key regulatory proteins and contribute to tumorigenesis. RING finger (RNF) proteins as E3 ubiquitin ligases, play fundamental roles in diverse biological processes, including cancer cell stemness. Through cancer epigenomic profiling, we identify tumor‐specific promoter CpG methylation of the E3 ligase RINES across multiple common cancer types (esophageal, nasopharyngeal, colorectal, breast, lung, kidney, cervical, and liver), in addition to previously reported gastric cancer, which correlates with poor patient survival. We further find that RINES inhibits tumor cell growth in vivo and in vitro. Mechanistically, RINES physically interacts with STAT3 and MYC to promote their protein degradation via its E3 ubiquitin ligase activity. RING domain‐dependent ubiquitin–proteasome degradation of STAT3 and MYC is essential for RINES‐mediated suppression of cancer stemness. Consistently, RINES knockdown diminishes the ubiquitination of STAT3 and MYC and elevates their protein stability, which enhances cancer stem cell properties and promotes tumorigenesis. Thus, our study establishes RINES as a bona fide tumor suppressor that directly modulates STAT3 and MYC stability to restrict cancer cell stemness. RINES promoter methylation may serve as a promising epigenetic biomarker for multiple common cancers.