SETDB1 cooperates with the CRL4B complex to promote colorectal cancer tumorigenesis by disrupting circadian rhythm.

The circadian rhythm is an intrinsic, self-regulatory physiological system in organisms that is hierarchically governed by core clock genes. Dysregulation of this rhythm is closely associated with tumor progression. However, the specific molecular mechanisms underlying circadian rhythm disruption-mediated colorectal cancer (CRC) remain largely elusive. The histone methyltransferase SET domain bifurcated 1 (SETDB1) exerts oncogenic functions in multiple solid tumors, prompting this study to investigate the molecular mechanisms through which SETDB1 regulates CRC progression. Our results demonstrate that SETDB1 acts as an oncogene in CRC by interacting with the Cullin 4B-RING E3 ligase (CRL4B) complex to enhance cancer cell proliferation, invasion, and stemness maintenance. Specifically, SETDB1 and the CRL4B complex assemble into a transcriptional repressor complex that binds to the promoters of core clock genes, such as PER3 and CRY1, to repress their transcription, thereby disrupting cellular circadian rhythms and ultimately accelerating CRC cell proliferation and metastasis. Collectively, our findings elucidate the pivotal role of the SETDB1/CRL4B complex in CRC pathogenesis and provide a potential therapeutic strategy targeting SETDB1 for patients with CRC with high CUL4B expression.