Abstract
Ovarian clear cell carcinoma (OCCC) is associated with a frequent loss in ARID1A function. ARID1A reportedly suppresses histone deacetylase (HDAC)6 in OCCC directly. Here, we evaluated the clinical significance of HDAC6 expression and its related factors in terms of ARID1A status. Immunohistochemical expression of HDAC6, hypoxia inducible factors-1α (HIF-1α), programmed death-1 ligand (PD-L1), CD44 (cancer stem cell marker), and ARID1A was analysed for 106 OCCC patients. High nuclear HDAC6 expression correlated with patient death (p = 0.038). In the multivariate analysis of overall survival, surgical status (complete or incomplete resection) (hazard ratio (HR) = 17.5; p = <0.001), HDAC6 nuclear expression (HR = 1.68; p = 0.034), and PD-L1 expression (HR = 1.95; p = 0.022) were the independent prognostic factors. HDAC6 upregulation and ARID1A loss did not necessarily occur simultaneously. High HDAC6 expression was associated with poor prognosis in OCCC with ARID1A loss; this was not observed without ARID1A loss. HDAC6 expression showed a significant positive correlation with HIF-1α, PD-L1, and CD44. In OCCC, HDAC6 involvement in prognosis depended on ARID1A status. HDAC6 also led to immuno- and hypoxia- tolerance and cancer stem cell phenotype. HDAC6 is a promising therapeutic target for OCCC with loss of ARID1A.
Highlights
Ovarian clear cell carcinoma (OCCC) ranks second as the leading cause of death from epithelial ovarian cancer (EOC)[1] and is associated with the worst prognosis among the major subtypes of EOC when diagnosed at the advanced stages[2,3]
OCCC patients with high nuclear expression of HDAC6 had a poor prognosis regardless of Federation of Obstetrics and Gynaecology (FIGO) stage and surgical status, the latter of which is a well-known important prognostic factor in EOC. These results suggest that HDAC6 is one of the refractory factors to the standard treatments in OCCC
The standard chemotherapy for EOC is a combination of platinum and taxane agents; OCCC patients are resistant to this combination
Summary
Ovarian clear cell carcinoma (OCCC) ranks second as the leading cause of death from epithelial ovarian cancer (EOC)[1] and is associated with the worst prognosis among the major subtypes of EOC when diagnosed at the advanced stages[2,3]. The pan-HDAC inhibitor has been demonstrated to exhibit cytotoxic effects in various cancers, including EOC12. Its activities of targeting multiple HDACs lead to various toxicities, which limits its application in the treatment of cancers[13]. This in turn enhances microtubule dynamics and leads to cancer cell growth (Fig. 1)[15,16]. Bitler et al.[23] identified that ARID1A directly suppresses HDAC6 in OCCC and provided evidence that HDAC6 may be a promising therapeutic target in ARID1A-mutated cancers. The significance of the association between HDAC6 and ARID1A has not been well documented in clinical samples. We investigated the significance of HDAC6 as a therapeutic target in OCCC and the usefulness of ARID1A as its biomarker using clinical samples
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