Vorinostat decrease M2 macrophage polarization through ARID1A^6488delG/HDAC6/IL-10 signaling pathway in...

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Endometriosis is linked to ovarian cancer, with ARID1A mutations and HDAC6 expression implicated in its pathogenesis.
• The precise molecular mechanisms connecting endometriosis, ARID1A, and ovarian cancer progression remain unclear.

Purpose of the Study:

• To elucidate the role of HDAC6 in endometriosis-associated ovarian carcinoma (EAOC) and evaluate the therapeutic potential of HDAC inhibitors.
• To investigate the signaling pathway involving E4F1/ARID1A/HDAC6/GATA3 in macrophage polarization within the context of EAOC.

Main Methods:

• Analysis of clinical EAOC samples to correlate HDAC6 expression with clinicopathological features and survival.
• In vitro studies using cell models to assess the impact of ARID1A mutation and HDAC6 on macrophage polarization (IL-10).
• Evaluation of the HDAC inhibitor vorinostat on cell growth, apoptosis, and M2 macrophage polarization in vitro and in a transgenic mouse model of EAOC.

Main Results:

• High HDAC6 expression correlated with advanced EAOC histology, stage, tumor size, and poorer survival.
• ARID1A mutation and HDAC6 were found to induce M2 macrophage polarization through IL-10.
• Vorinostat treatment inhibited EAOC cell growth, induced apoptosis, and significantly reduced tumor size in mice by suppressing M2 macrophage polarization.

Conclusions:

• The E4F1/ARID1A/HDAC6/GATA3 pathway mediates macrophage polarization in EAOC.
• Targeting IL-10 offers a novel immune cell-associated therapeutic strategy for EAOC.
• HDAC inhibitors like vorinostat represent a promising therapeutic approach for EAOC.