2. Academic Validation
  3. Targeted degradation of GOLM1 by CC-885 via CRL4-CRBN E3 ligase inhibits hepatocellular carcinoma progression

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

  • Cell Signal. 2025 Jun:130:111665. doi: 10.1016/j.cellsig.2025.111665.
Jingliang He 1,  Jingli Guo 2,  Shunfang Liu 3,  Hanxue Li 1,  Yuanyuan Ma 4,  Shaojie Ma 1,  Zhongke Hu 1,  Wensi Zhao 5,  Minjia Tan 6,  Wei Liu 7,  Bin Liu 8
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China.
  • 2 Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China; Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road 1095, Wuhan 430030, China.
  • 4 Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
  • 5 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 7 Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: weiliu@mcw.edu.
  • 8 Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China. Electronic address: liubin@jou.edu.cn.
PMID: 39986359 DOI: 10.1016/j.cellsig.2025.111665
Abstract

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.

Keywords

Apoptosis; CC-885; CRBN; GOLM1; Hepatocellular carcinoma; Ubiquitination.

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