Targeted degradation of GOLM1 by CC-885 via CRL4-CRBN E3 ligase inhibits hepatocellular carcinoma progression

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, emphasizing the urgent need for novel therapeutic strategies. In this study, we investigate the anti-tumor potential of CC-885, a cereblon (CRBN) modulator known for its efficacy in targeting neoplastic cells through proteasomal degradation pathways. Our findings demonstrate that CC-885 exhibits potent anti-tumor activity against HCC. In vitro assays revealed that CC-885 significantly inhibits the proliferation, migration, and invasion of HCC cells. These effects were corroborated in vivo, where CC-885 markedly suppressed tumor growth and angiogenesis in chick embryos and impeded the progression of orthotopic liver tumors in murine models. Mechanistically, CC-885 selectively reduces GOLM1 protein levels via ubiquitin-mediated proteasomal degradation. Knockdown of GOLM1 recapitulated the anti-proliferative effects of CC-885, while overexpression of GOLM1 conferred resistance to CC-885-induced apoptosis and growth inhibition. Further investigation revealed that CC-885 facilitates the interaction between GOLM1 and the E3 ubiquitin ligase CRBN, promoting the ubiquitination and subsequent degradation of GOLM1. Transcriptomic analyses showed that both CC-885 treatment and GOLM1 knockdown modulate critical pathways involved in apoptosis. These findings position CC-885 as a promising therapeutic candidate for HCC, acting primarily through CRBN-dependent degradation of GOLM1, and support its further development for clinical application. • CC-885 demonstrates significant antitumor activity against hepatocellular carcinoma (HCC) cells by inhibiting proliferation, migration, and invasion both in vitro and in vivo. • CC-885 induces the degradation of GOLM1 via the CRL4-CRBN E3 ubiquitin ligase complex. • GOLM1 identified as a critical target for CC-885, with knockdown replicating the drug's effects and overexpression conferring resistance. • Transcriptomic analysis shows that both CC-885 treatment and GOLM1 knockdown affect pathways involved in apoptosis. • Clinical relevance is highlighted by the association of high GOLM1 expression with poor prognosis in HCC patients, positioning CC-885 as a potential therapeutic agent.