Co‐occurrence of BAP1 and SF3B1 mutations in uveal melanoma induces cellular senescence

Molecular Oncology

Zhonglu Ren¹  Joan Heller Brown²  Toshiro Moroishi²  Steven W. Plouffe²  Kun‐Liang Guan²  Zhipeng Meng²  Yilei Li³  Yiyue Zhang⁴  Peng Liu⁵  Dan Zhou⁶  Xin Luo⁶  Shuwen Liu⁶  Guiming Zhang⁶  Le Yu⁶ 

[1] College of Medical Information Engineering Guangdong Pharmaceutical University Guangzhou China;Department of Pharmacology and Moores Cancer Center University of California San Diego CA USA;Department of Pharmacy Nanfang Hospital Southern Medical University Guangzhou China;Division of Cell Development and Integrative Biology School of Medicine South China University of Technology Guangzhou China;Institutes of Biomedical Sciences Fudan University Shanghai China;School of Pharmaceutical Sciences Southern Medical University Guangzhou China;

关键词: BAP1;    mutually exclusive pattern;    recurrent mutations;    senescence;    SF3B1;    uveal melanoma;   

DOI  :  10.1002/1878-0261.13128

来源: DOAJ

【 摘 要 】

Uveal melanoma (UM) is the most common intraocular tumor in adults. Recurrent mutations in BRCA1‐associated protein 1 (BAP1) and splicing factor 3B subunit 1 (SF3B1) display a mutually exclusive pattern in UM, but the underlying mechanism is unknown. We show that combined BAP1 deficiency and SF3B1 hotspot mutation lead to senescence and growth arrest in human UM cells. Although p53 protein expression is induced, deletion of TP53 (encoding p53) only modestly rescues the observed senescent phenotype. UM cells with BAP1 loss or SF3B1 mutation are more sensitive to chemotherapeutic drugs compared with their isogenic parental cells. Transcriptome analysis shows that DNA‐repair genes are downregulated upon co‐occurrence of BAP1 deletion and SF3B1 mutation, thus leading to impaired DNA damage response and the induction of senescence. The co‐occurrence of these two mutations reduces invasion of UM cells in zebrafish xenograft models and suppresses growth of melanoma xenografts in nude mice. Our findings provide a mechanistic explanation for the mutual exclusivity of BAP1 and SF3B1 mutations in human UM.

【 授权许可】

Unknown