Targeted degradation of GOLM1 by CC-885 via CRL4-CRBN E3 ligase inhibits hepatocellular carcinoma progression. Cell Signal 2025 Jun;130:111665
Date
02/23/2025Pubmed ID
39986359DOI
10.1016/j.cellsig.2025.111665Scopus ID
2-s2.0-85218907304 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
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.
Author List
He J, Guo J, Liu S, Li H, Ma Y, Ma S, Hu Z, Zhao W, Tan M, Liu W, Liu BAuthor
Wei Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAnimals
Apoptosis
Carcinoma, Hepatocellular
Cell Line, Tumor
Cell Movement
Cell Proliferation
Chick Embryo
Disease Progression
Humans
Liver Neoplasms
Membrane Proteins
Mice
Mice, Nude
Proteolysis
Ubiquitin-Protein Ligases
Ubiquitination
