2. Academic Validation
  3. Sequential targeting of YAP1 and p21 enhances the elimination of senescent cells induced by the BET inhibitor JQ1

Sequential targeting of YAP1 and p21 enhances the elimination of senescent cells induced by the BET inhibitor JQ1

  • Cell Death Dis. 2021 Jan 25;12(1):121. doi: 10.1038/s41419-021-03416-1.
Huan-Tian Zhang  # 1 2 3,  Tao Gui  # 4 5,  Ri-Xu Liu 4 5,  Kui-Leung Tong 5,  Chong-Jie Wu 4 5,  Zhenyan Li 4 5,  Xun Huang 6,  Qiu-Tong Xu 4 5,  Jie Yang 4 5,  Wang Tang 4 5,  Yuan Sang 7,  Wanting Liu 8,  Ning Liu 4 5,  Ryan D Ross 9,  Qing-Yu He 10,  Zhen-Gang Zha 11 12
Affiliations

Affiliations

  • 1 Institute of Orthopedic Diseases, Jinan University, Guangzhou, China. zhanghuantian@jnu.edu.cn.
  • 2 Center for Joint Surgery and Sports Medicine, the First Affiliated Hospital, Jinan University, Guangzhou, China. zhanghuantian@jnu.edu.cn.
  • 3 Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, College of Life Science and Technology, Jinan University, Guangzhou, China. zhanghuantian@jnu.edu.cn.
  • 4 Institute of Orthopedic Diseases, Jinan University, Guangzhou, China.
  • 5 Center for Joint Surgery and Sports Medicine, the First Affiliated Hospital, Jinan University, Guangzhou, China.
  • 6 Shandong Provincial Key Laboratory of Detection Technology for Tumor Markers, College of Chemistry and Chemical Engineering, Linyi University, Linyi, China.
  • 7 Department of Joint Replacement and Trauma Surgery, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 8 Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, College of Life Science and Technology, Jinan University, Guangzhou, China.
  • 9 Department of Cell and Molecular Medicine, Rush University Medical Center, Chicago, IL, USA.
  • 10 Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, College of Life Science and Technology, Jinan University, Guangzhou, China. tqyhe@jnu.edu.cn.
  • 11 Institute of Orthopedic Diseases, Jinan University, Guangzhou, China. zhzgg@vip.163.com.
  • 12 Center for Joint Surgery and Sports Medicine, the First Affiliated Hospital, Jinan University, Guangzhou, China. zhzgg@vip.163.com.
  • # Contributed equally.
PMID: 33495462 DOI: 10.1038/s41419-021-03416-1
Abstract

Chondrosarcoma (CHS) is the second most common bone malignancy with limited therapeutic approaches. Our previous study has found that Yes associated protein 1 (YAP1) is downregulated in CHS cells treated with bromodomain and extraterminal domain (BET) inhibitor JQ1. However, the precise role of YAP1 in CHS is largely unknown. Herein, we found that YAP1 expression was upregulated in CHS tissues, and positively correlated with its grading score. Loss of YAP1 inhibited CHS proliferation and induced cellular senescence, while expression of YAP1 mutants revealed YAP1/TEA domain family member (TEAD)-dependent negative regulation of p21 and subsequent cellular senescence. These results were validated by in vivo experiments using stable shYAP1 cell lines. Mechanistically, negative regulation of p21 by YAP1 occurred post-transcriptionally via Dicer-regulated miRNA networks, specifically, the miR-17 family. Furthermore, we demonstrated that sequential targeting of YAP1 and p21 enhanced the elimination of JQ1-induced senescent cells in a Bcl-2-like 1 (Bcl-xL)/Caspase-3 dependent manner. Altogether, we unveil a novel role of YAP1 signaling in mediating CHS cell senescence and propose a one-two punch approach that sequentially targets the YAP1/p21 axis to eliminate senescent cells.

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