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Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer

Takeshi Fukumoto1, Pyoung Hwa Park1, Shuai Wu1

  • 1Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.

Cell Reports
|March 29, 2018
PubMed

Insights

Mutations in ARID1A (a SWI/SNF complex subunit) make ovarian cancers sensitive to HDAC inhibitors like SAHA. This approach suppressed tumor growth and improved survival in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • ARID1A is frequently mutated in ovarian clear cell carcinomas (OCCCs), a cancer lacking effective treatments.
  • SWI/SNF complex dysfunction, particularly ARID1A mutations, is a hallmark of various cancers.

Purpose of the Study:

  • To investigate the therapeutic potential of pan-Histone Deacetylase (HDAC) inhibitors in ARID1A-mutated ovarian cancers.
  • To elucidate the molecular mechanisms linking ARID1A status, HDAC2 activity, and tumor suppressor gene expression.

Main Methods:

  • Assessed sensitivity of ARID1A-mutated ovarian cancer cells to SAHA (a pan-HDAC inhibitor).
  • Investigated the interaction between HDAC2 and EZH2 in an ARID1A-dependent manner.
  • Utilized orthotopic and genetic mouse models of ARID1A-inactivated OCCCs to evaluate SAHA efficacy.

Main Results:

  • ARID1A mutations confer sensitivity to pan-HDAC inhibitors, with SAHA inducing significant growth suppression.
  • HDAC2 acts as an EZH2 co-repressor, suppressing tumor suppressor genes like PIK3IP1 in an ARID1A-dependent manner.
  • SAHA treatment reduced tumor growth, ascites, and improved survival in preclinical models of ARID1A-mutated OCCCs.

Conclusions:

  • ARID1A inactivation sensitizes ovarian cancers to HDAC inhibition, specifically targeting HDAC2.
  • Repurposing FDA-approved pan-HDAC inhibitors like SAHA presents a promising therapeutic strategy for ARID1A-mutated cancers.
  • Targeting the HDAC2-EZH2 axis offers a novel therapeutic avenue for ARID1A-deficient ovarian clear cell carcinomas.
Keywords:
ARID1AHDAC2SAHASWI/SNFchromatin remodelingovarian cancerpan-HDAC inhibitor

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