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Allosteric Hsp70 Modulator YM-1 Induces Degradation of BRD4

Yugo Mishima1, Shusuke Tomoshige1, Shinichi Sato1,2

  • 1Graduate School of Life Sciences, Tohoku University.

Chemical & Pharmaceutical Bulletin
|January 31, 2024
PubMed

Insights

YM-1, a heat-shock 70 kDa protein (Hsp70) modulator, triggers cancer cell death by promoting the degradation of bromodomain containing 4 (BRD4). This mechanism involves Hsp70, CHIP, and BRD4 ubiquitination, leading to reduced oncogene expression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Heat-shock 70 kDa protein (Hsp70) is a crucial molecular chaperone implicated in cancer.
  • YM-1 is an allosteric modulator of Hsp70 with known anticancer properties, but its precise mechanism of action remains unclear.
  • Bromodomain containing 4 (BRD4) is a key regulator of oncogene expression and a validated therapeutic target in various cancers.

Purpose of the Study:

  • To elucidate the molecular mechanism by which YM-1 inhibits cancer cell growth.
  • To investigate the role of Hsp70 and its interacting partners in YM-1-mediated anti-cancer effects.
  • To determine if YM-1 affects the stability or expression of BRD4.

Main Methods:

  • Cell-based assays to assess cancer cell viability and proliferation.
  • Western blotting and immunoprecipitation to detect protein-protein interactions and degradation.
  • Ubiquitination assays to identify the role of E3 ligases.
  • Quantitative real-time PCR to measure gene expression levels.

Main Results:

  • YM-1 treatment led to the degradation of BRD4 in cancer cells.
  • YM-1 enhanced the binding between Hsp70 and BRD4.
  • Hsp70-mediated recruitment of C-terminus of Hsc70-interacting protein (CHIP) resulted in BRD4 ubiquitination and subsequent proteasomal degradation.
  • The decrease in BRD4 levels correlated with reduced oncogene expression and inhibited cancer cell growth.

Conclusions:

  • YM-1 inhibits cancer cell growth by inducing the proteasomal degradation of BRD4.
  • The mechanism involves the formation of an Hsp70-BRD4 complex, facilitating BRD4 ubiquitination by CHIP.
  • Targeting the Hsp70-BRD4-CHIP axis represents a potential therapeutic strategy for cancers driven by BRD4.
Keywords:
YM-1bromodomain containing 4 (BRD4)cancer treatmentheat-shock 70 kDa protein (Hsp70)protein degradation

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