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Published on: March 15, 2024

Divergent roles of SPOP and CHD1 in ACSL4 regulation reveal context-dependent vulnerabilities for targeting

Feiyu Chen1, Qidong Li1, Qianlin Gu1

  • 1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Nature Communications
|June 30, 2026
PubMed

Insights

Genetic mutations in SPOP and CHD1 influence prostate cancer

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Prostate cancer (PCa) exhibits genetic heterogeneity impacting treatment outcomes.
  • SPOP mutations and CHD1 deletions define PCa subtypes with varied responses to anti-androgen therapy.
  • Ferroptosis, a cell death pathway, presents a novel anticancer strategy.

Purpose of the Study:

  • To investigate the role of SPOP mutations and CHD1 deletions in ferroptosis susceptibility in prostate cancer.
  • To elucidate the molecular mechanisms by which SPOP and CHD1 regulate ferroptosis.
  • To explore therapeutic strategies combining ferroptosis inducers with agents targeting cholesterol metabolism.

Main Methods:

  • Utilized genetically engineered human and murine models of prostate cancer.
  • Investigated the effects of SPOP mutations and CHD1 deletion on ferroptosis inducer efficacy (targeting GPX4).
  • Analyzed the regulation of the MYC-ACSL4 axis and its role in ferroptosis.

Main Results:

  • SPOP mutations increase, while CHD1 deletions decrease, ferroptosis susceptibility in PCa.
  • SPOP and CHD1 antagonistically regulate the MYC-ACSL4 axis, controlling ferroptosis.
  • Targeting cholesterol metabolism with cholesterol-lowering agents re-sensitized SPOP/CHD1 co-deficient tumors to ferroptosis inducers by restoring ACSL4 expression.

Conclusions:

  • SPOP and CHD1 act as key upstream genetic regulators of ferroptosis in prostate cancer.
  • Combinatorial strategies targeting cholesterol metabolism and ferroptosis show promise for advanced PCa.
  • Biomarker-driven approaches using SPOP/CHD1 status can guide ferroptosis-based therapy selection.

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