2. Academic Validation
  3. A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells

A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells

  • Nat Commun. 2020 Apr 22;11(1):1935. doi: 10.1038/s41467-020-15719-6.
Masahiro Wakita 1,  Akiko Takahashi 2,  Osamu Sano 3,  Tze Mun Loo 2,  Yoshinori Imai 2,  Megumi Narukawa 1,  Hidehisa Iwata 3,  Tatsuyuki Matsudaira 1 4,  Shimpei Kawamoto 1,  Naoko Ohtani 5,  Tamotsu Yoshimori 6,  Eiji Hara 7 8 9
Affiliations

Affiliations

  • 1 Research Institute for Microbial Diseases (RIMD), Osaka University, Suita, 565-0871, Japan.
  • 2 Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan.
  • 3 BioMolecular Research Laboratories, Takeda Pharmaceutical Company Ltd., Fujisawa, 251-8555, Japan.
  • 4 Immunology Frontier Research Center (IFReC), Osaka University, Suita, 565-0871, Japan.
  • 5 Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan.
  • 6 Graduate School of Medicine, Osaka University, Suita, 565-0871, Japan.
  • 7 Research Institute for Microbial Diseases (RIMD), Osaka University, Suita, 565-0871, Japan. ehara@biken.osaka-u.ac.jp.
  • 8 Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan. ehara@biken.osaka-u.ac.jp.
  • 9 Immunology Frontier Research Center (IFReC), Osaka University, Suita, 565-0871, Japan. ehara@biken.osaka-u.ac.jp.
PMID: 32321921 DOI: 10.1038/s41467-020-15719-6
Abstract

Although cellular senescence acts primarily as a tumour suppression mechanism, the accumulation of senescent cells in vivo eventually exerts deleterious side effects through inflammatory/tumour-promoting factor secretion. Thus, the development of new drugs that cause the specific elimination of senescent cells, termed senolysis, is anticipated. Here, by an unbiased high-throughput screening of chemical compounds and a bio-functional analysis, we identify BET family protein degrader (BETd) as a promising senolytic drug. BETd provokes senolysis through two independent but integrated pathways; the attenuation of non-homologous end joining (NHEJ), and the up-regulation of autophagic gene expression. BETd treatment eliminates senescent hepatic stellate cells in obese mouse livers, accompanied by the reduction of liver Cancer development. Furthermore, the elimination of chemotherapy-induced senescent cells by BETd increases the efficacy of chemotherapy against xenograft tumours in immunocompromised mice. These results reveal the vulnerability of senescent cells and open up possibilities for its control.

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