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  3. Deciphering the regulatory mechanisms and biological implications of ARID1A missense mutations in cancer

Deciphering the regulatory mechanisms and biological implications of ARID1A missense mutations in cancer

  • Cell Rep. 2024 Oct 29;43(11):114916. doi: 10.1016/j.celrep.2024.114916.
Fang Liu 1,  Jun Ying 2,  Kai Yang 3,  Xinyuan Xiong 4,  Nan Yang 4,  Shu Wang 4,  Wenzhen Zhao 4,  Huiqin Zhu 4,  Ming Yu 4,  Jun Wu 5,  Jie Yang 6,  Xiaonan Wang 7,  Xuxu Sun 8
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Laboratory Medicine, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201803, China.
  • 2 School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 3 Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 4 Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 5 Department of Laboratory Medicine, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201803, China.
  • 6 Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: yangjieyj@shsmu.edu.cn.
  • 7 School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: xiaonanwang@shsmu.edu.cn.
  • 8 Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Laboratory Medicine, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201803, China. Electronic address: xuxu.sun@shsmu.edu.cn.
PMID: 39475510 DOI: 10.1016/j.celrep.2024.114916
Abstract

ARID1A is a key component of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex and functions as a critical tumor suppressor in various cancers. In this study, we find that tumor cells with hotspot missense mutations in ARID1A (AT-rich interactive domain-containing protein 1A) exhibit a malignant phenotype. Mechanistically, these mutations facilitate the translocation of ARID1A mutant proteins to the cytoplasm by the nucleocytoplasmic shuttler XPO1 (exportin 1). Subsequently, the E3 ubiquitin Ligase STUB1 ubiquitinates the ARID1A mutant protein, marking it for degradation. Knocking down STUB1 or inhibiting XPO1 stabilizes the ARID1A mutant protein, retaining it in the nucleus, which restores the assembly of the cBAF complex, the chromatin remodeling function, and the normal expression of genes related to the MAPK and anti-apoptotic pathways, thereby decreasing the tumor burden. Our research shows that nuclear-localized mutated ARID1A proteins retain tumor-suppressive function. We identify promising strategies to treat cancers harboring missense mutations in the BAF complex.

Keywords

ARID1A; CP: Cancer; CP: Genomics; STUB1; SWI/SNF complex; cancer; missense mutation.

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