ARID1A-mutated ovarian cancers depend on HDAC6 activity

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• ARID1A is a frequently mutated epigenetic regulator in human cancers, often mutually exclusive with TP53 mutations.
• The therapeutic implications of ARID1A mutations, particularly in relation to TP53, are not well understood.
• Chromatin remodeling complexes, like SWI/SNF, play critical roles in cancer development.

Purpose of the Study:

• To investigate the functional dependence of ARID1A-mutated cancers on HDAC6.
• To evaluate the therapeutic potential of HDAC6 inhibition in ARID1A-mutated cancers.
• To elucidate the molecular mechanisms linking ARID1A mutations, HDAC6 activity, and apoptosis.

Main Methods:

• Utilized a clinically applicable small-molecule inhibitor of HDAC6.
• Assessed tumor growth, dissemination, and survival in mouse models with ARID1A-mutated tumors.
• Investigated the transcriptional regulation of HDAC6 by ARID1A.
• Examined the effect of HDAC6 inhibition on apoptosis and p53 post-translational modifications.

Main Results:

• HDAC6 activity is essential for the survival and growth of ARID1A-mutated ovarian cancers.
• HDAC6 inhibition significantly improved survival and suppressed tumor growth and dissemination in preclinical models.
• ARID1A directly represses HDAC6 transcription, leading to its upregulation in ARID1A-mutated cells.
• HDAC6 inhibition selectively induced apoptosis in ARID1A-mutated cells by preventing deacetylation of pro-apoptotic p53 (Lys120).

Conclusions:

• HDAC6 is a critical therapeutic target for ARID1A-mutated cancers.
• Pharmacological inhibition of HDAC6 represents a promising strategy for treating ARID1A-mutated cancers.
• The ARID1A-HDAC6-p53 axis offers a novel therapeutic vulnerability in these cancers.