2. Academic Validation
  3. RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylation

RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylation

  • Cell Discov. 2024 Mar 19;10(1):32. doi: 10.1038/s41421-024-00654-3.
Peng Lin # 1 2 3,  Wenyan Chen # 4,  Zhilin Long 2 3,  Jichuan Yu 2 3,  Jiayao Yang 2 3,  Zhen Xia 2 3,  Qiulian Wu 5,  Xinyu Min 2,  Jing Tang 3,  Ya Cui 6,  Fuyi Liu 7,  Chun Wang 7,  Jian Zheng 7,  Wei Li 6,  Jeremy N Rich 8,  Lei Li 9,  Qi Xie 10 11
Affiliations

Affiliations

  • 1 College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
  • 2 Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.
  • 3 Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
  • 4 Shenzhen Bay Laboratory, Shenzhen, Guangdong, China.
  • 5 University of Pittsburgh Medical Center Hillman Cancer Center, Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 6 Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA.
  • 7 Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 8 University of Pittsburgh Medical Center Hillman Cancer Center, Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA. drjeremyrich@gmail.com.
  • 9 Shenzhen Bay Laboratory, Shenzhen, Guangdong, China. lei.li@szbl.ac.cn.
  • 10 Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China. xieqi@westlake.edu.cn.
  • 11 Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China. xieqi@westlake.edu.cn.
  • # Contributed equally.
PMID: 38503731 DOI: 10.1038/s41421-024-00654-3
Abstract

Glioblastoma is one of the most lethal malignant cancers, displaying striking intratumor heterogeneity, with glioblastoma stem cells (GSCs) contributing to tumorigenesis and therapeutic resistance. Pharmacologic modulators of ubiquitin ligases and deubiquitinases are under development for Cancer and Other Diseases. Here, we performed parallel in vitro and in vivo CRISPR/Cas9 knockout screens targeting human ubiquitin E3 Ligases and deubiquitinases, revealing the E3 Ligase RBBP6 as an essential factor for GSC maintenance. Targeting RBBP6 inhibited GSC proliferation and tumor initiation. Mechanistically, RBBP6 mediated K63-linked ubiquitination of Cleavage and Polyadenylation Specific Factor 3 (CPSF3), which stabilized CPSF3 to regulate alternative polyadenylation events. RBBP6 depletion induced shortening of the 3'UTRs of MYC competing-endogenous RNAs to release miR-590-3p from shortened UTRs, thereby decreasing MYC expression. Targeting CPSF3 with a small molecular inhibitor (JTE-607) reduces GSC viability and inhibits in vivo tumor growth. Collectively, RBBP6 maintains high MYC expression in GSCs through regulation of CPSF3-dependent alternative polyadenylation, providing a potential therapeutic paradigm for glioblastoma.

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