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Squamocin Suppresses Tumor Growth through Triggering an Endoplasmic Reticulum Stress-Associated Degradation of

Yin Zhu1,2, Yurui Liu1,2, Xiangtao Wang3

  • 1School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|January 17, 2025
PubMed

Insights

Squamocin depletes EZH2 and MYC oncoproteins by disrupting mitochondrial function and triggering endoplasmic reticulum stress. This mechanism enhances protein degradation, offering a new therapeutic strategy for cancers driven by the EZH2/MYC axis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Annonaceous acetogenins (ACGs) show antitumor potential, but their clinical use is limited by unknown mechanisms of action.
  • Squamocin, an ACG, has demonstrated efficacy against various cancers, including head and neck, gastric, and colorectal cancers.

Purpose of the Study:

  • To elucidate the molecular mechanism by which squamocin exerts its antitumor effects.
  • To identify the direct binding target of squamocin and its downstream signaling pathways.

Main Methods:

  • Surface Plasmon Resonance (SPR), Differential Scanning Fluorimetry (DSF), and Cellular Thermal Shift Assay (CETSA) were used to identify squamocin's direct binding target.
  • Mitochondrial function assays, ATP production measurements, and ER stress markers were analyzed.
  • Ubiquitin-proteasome system components (UBA6, UBE2Z, FBXW7) and oncoprotein levels (EZH2, MYC) were assessed.

Main Results:

  • Squamocin directly binds to heat shock protein 90α (HSP90α).
  • Squamocin disrupts mitochondrial Complex I, reduces ATP, and impairs HSP90α function, leading to ER stress and the unfolded protein response (UPR).
  • This cascade activates the UBA6-UBE2Z-FBXW7 ubiquitin pathway, promoting the degradation of oncoproteins EZH2 and MYC.

Conclusions:

  • Squamocin induces cancer cell death by triggering an ER stress-mediated ubiquitin cascade that degrades EZH2 and MYC.
  • The findings reveal a novel mechanism for squamocin's anticancer activity and highlight its potential for targeting EZH2/MYC-driven tumors.
Keywords:
EZH2/MYC axisannonaceous acetogeninsendoplasmic reticulum stress responsesquamocinubiquitin‐proteasome degradation system

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