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MAP4 phosphorylation induced by ARID1A loss sensitizes colorectal cancer cells to EMP

Lei Pan1,2, Danzhu Wu1, Yilin He1

  • 1Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Cell Death & Disease
|December 8, 2025
PubMed

Insights

Loss of the ARID1A tumor suppressor gene creates a vulnerability to estramustine phosphate sodium (EMP). This chemotherapy drug targets MAP4, disrupting microtubule dynamics and inducing cell death in ARID1A-deficient cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Mutational inactivation of the ARID1A gene drives tumorigenesis in multiple cancers.
  • ARID1A is a promising therapeutic target for novel anticancer drug development.

Purpose of the Study:

  • To identify synthetic lethal drug partners for ARID1A-deficient cancers.
  • To elucidate the mechanism underlying the synthetic lethality between ARID1A loss and estramustine phosphate sodium (EMP).

Main Methods:

  • Conducted a synthetic lethal drug screening using ARID1A isogenic colorectal cancer cell lines and an FDA-approved drug library.
  • Investigated the role of microtubule-associated protein 4 (MAP4) phosphorylation and its regulation by PI3K in ARID1A-deficient cells.

Main Results:

  • Identified estramustine phosphate sodium (EMP) as a synthetic lethal partner of ARID1A.
  • Demonstrated that ARID1A loss increases MAP4 phosphorylation, leading to impaired microtubule stabilization and dependence on residual MAP4 activity.
  • Showed that EMP targets MAP4, disrupting microtubule dynamics and inducing mitotic cell death in ARID1A-deficient cells.
  • Revealed that PI3K, activated by ARID1A loss, phosphorylates MAP4.

Conclusions:

  • ARID1A loss confers sensitivity to EMP through dysregulation of MAP4-mediated microtubule dynamics.
  • MAP4 is a key regulator of microtubule dynamics in ARID1A-deficient cells.
  • A novel synthetic lethality relationship between ARID1A and EMP has been uncovered, offering a potential therapeutic strategy.

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