Clinicopathological correlation of ARID1A status with HDAC6 and its related factors in ovarian clear cell carcinoma

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.

Figure 1

Scheme of HDAC6 functions: When ARID1A loss occurs, suppression of HDAC6 is relieved. In the nucleus, HDAC6 destabilizes p53 by deacetylation, and suppresses apoptosis. As a member of the HDAC family, HDAC6 inactivates chromatin by deacetylation of the core histones. These effects of HDAC6 in the nucleus are responsible for the resistance to platinum agents. In the cytoplasm, HDAC6 leads to cell proliferation, angiogenesis, glucose metabolism, glucose transport, and CSC phenotypes via tubulin, HIF-1α, PD-L1, and CD44. In addition, HDAC6 result in tolerance to taxane agents, cytotoxic T cells, immuno-checkpoints inhibitors, and hypoxic stress.

Figure 2

Kaplan-Meier survival analysis: Nuclear HDAC6 in (A) all cases, (B) with, and (C) without ARID1A loss. Cytoplasmic HDAC6 in (D) all cases, (E) with, and (F) without ARID1A loss. HIF-1α in (G) all cases, (H) with, and (I) without ARID1A loss. p values, log rank test.

Figure 3

Correlations among IHC expressions, using the Chi-square test.

Figure 4

IHC expressions. HDAC6 ((A) low; (B) high), ARID1A ((C) loss; (D) positive), HIF-1α ((E) low; (F) high), PD-L1 ((G) low; (H) high), and CD44 ((I) low; (J) high).