Abstract
Aberrant histone acetylation plays an essential role in the neoplastic process via the epigenetic silencing of tumour suppressor genes (TSGs); therefore, the inhibition of histone deacetylases (HDAC) has become a promising target in cancer therapeutics. To investigate the correlation of histone acetylation with clinicopathological features and TSG expression, we examined the expression of acetylated H3 (AcH3), RARβ2, E-cadherin, and β-catenin by immunohistochemistry in 65 cervical squamous cell carcinoma patients. The results revealed that the absence of AcH3 was directly associated with poor histological differentiation and nodal metastasis as well as reduced/negative expression of RARβ2, E-cadherin, and β-catenin in clinical tumour samples. We further demonstrated that the clinically available HDAC inhibitors valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA), in combination with all-trans retinoic acid (ATRA), can overcome the epigenetic barriers to transcription of RARβ2 in human cervical cancer cells. Chromatin immunoprecipitation analysis showed that the combination treatment increased the enrichment of acetylated histone in the RARβ2-RARE promoter region. In view of these findings, we evaluated the antitumor effects induced by combined VPA and ATRA treatment in a xenograft model implanted with poorly differentiated human squamous cell carcinoma. Notably, VPA restored RARβ2 expression via epigenetic modulation. Additive antitumour effects were produced in tumour xenografts by combining VPA with ATRA treatment. Mechanistically, the combination treatment reactivated the expression of TSGs RARβ2, E-cadherin, P21CIP1, and P53 and reduced the level of p-Stat3. Sequentially, upregulation of involucrin and loricrin, which indicate terminal differentiation, strongly contributed to tumour growth inhibition along with partial apoptosis. In conclusion, targeted therapy with HDAC inhibitors and RARβ2 agonists may represent a novel therapeutic approach for patients with cervical squamous cell carcinoma.
Highlights
Recent studies have suggested that alteration in the chromatin structure resulting from histone acetylation may be important for the neoplastic process [1,2,3]
A concomitant increase in the levels of P21CIP1, P53, and activated caspase 3 as well as a decrease in the levels of p-Stat3 and Bcl2 were noted (Figure 6D). These results indicate that histone deacetylase (HDAC) inhibitors and all-trans retinoic acid (ATRA) reactivate RARb2 via histone modification and sequentially upregulate other tumour suppressor genes (TSGs), thereby restoring the function of key regulatory pathways for cell differentiation and apoptosis, which contribute to the inhibition of tumor xenografts
We designed this study to quantify the level of acetylated histone H3 and the aberrant expression of RARb2 and the E-cadherin/b-catenin complex in biopsies of cervical squamous cell carcinoma patients using immunohistochemistry, to determine the relationship between the expression levels of these markers and the clinicopathological features of the patients, and to evaluate the therapeutic efficacy of the HDAC inhibitor valproic acid (VPA) combined with ATRA by targeting chromatin remodelling and retinoicacid receptor b (RARb) expression
Summary
Recent studies have suggested that alteration in the chromatin structure resulting from histone acetylation may be important for the neoplastic process [1,2,3]. Transcriptional silencing by histone deacetylation is one of the well-established mechanisms of TSG inactivation [1,5,6,7]. Some studies have shown that deacetylated histones at promoter regions suppress the expression of TSGs, such as retinoblastoma [8], retinoicacid receptor b (RARb) [9], p21 [10], p53 [6], p16 [11], E-cadherin [5], and many others.
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