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A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells
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A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells
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Journal Article
A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells
2020
Overview
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.
Senescent cells can influence the tumour microenvironment by secreting immunomodulatory factors and are thus a therapeutic target. Here, the authors identify a compound that degrades BET leading to DNA damage and activation of autophagy and a reduction in tumour growth.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ 13/89
/ Animals
/ Antineoplastic Agents - administration & dosage
/ Cell Cycle Proteins - antagonists & inhibitors
/ Cell Cycle Proteins - genetics
/ Cell Cycle Proteins - metabolism
/ Cellular Senescence - drug effects
/ DNA
/ DNA End-Joining Repair - drug effects
/ Homology
/ Humanities and Social Sciences
/ Humans
/ Mice
/ Proteins
/ Science
/ Transcription Factors - antagonists & inhibitors
/ Transcription Factors - genetics
/ Transcription Factors - metabolism
/ Tumors
