HERC4 suppresses colorectal cancer progression by promoting STAT3 ubiquitination

Ubiquitination, a critical post-translational modification, regulates diverse cellular processes including protein degradation, signal transduction, and cell cycle progression. Dysregulation of the ubiquitin system is closely associated with tumor development and progression. HERC4, a member of the HECT-type E3 ubiquitin Ligase family, remains poorly characterized in colorectal Cancer (CRC). In this study, we report that HERC4 is significantly downregulated in CRC tissues and is associated with unfavorable patient prognosis. Functional assays demonstrate that HERC4 suppresses CRC cell proliferation both in vitro and in vivo. Mechanistically, we identify that HERC4 directly interacts with STAT3 and promotes its ubiquitination via K48-linked polyubiquitin chains, leading to proteasomal degradation. Further mapping analysis reveals that lysine 392 (K392) on STAT3 is the specific ubiquitination site targeted by HERC4 This study not only highlights the biological significance of HERC4 in colorectal Cancer but also suggests the HERC4-STAT3 axis as a potential therapeutic target for intervention.