title: Targeting of histone deacetylases to reactivate tumour suppressor genes and its therapeutic potential in a human cervical cancer xenograft model.
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, P21 (CIP1) , 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.
authors.affiliation: Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Shandong, China ; Anhui Province Key Laboratory of Molecular Medicine, Anhui Provincial Hospital Affiliated to Anhui Medical University, Anhui, China.
authors.forename: Dingqing
authors.initials: D
authors.lastname: Feng
authors.forename: Jiao
authors.initials: J
authors.lastname: Wu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.forename: Hu
authors.initials: H
authors.lastname: Zhou
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.forename: Weiping
authors.initials: W
authors.lastname: Hu
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhao
authors.forename: Haiming
authors.initials: H
authors.lastname: Wei
authors.forename: Bin
authors.initials: B
authors.lastname: Ling
authors.forename: Chunhong
authors.initials: C
authors.lastname: Ma
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D049230:Retinoid X Receptor beta / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D014635:Valproic Acid / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015820:Cadherins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D049230:Retinoid X Receptor beta; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D014212:Tretinoin; D014635:Valproic Acid; D006655:Histone Deacetylases