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Cancer Cell International
Published in: Cancer Cell International 1/2022

Open Access 01-12-2022 | Primary research

Silencing of histone deacetylase 3 suppresses the development of esophageal squamous cell carcinoma through regulation of miR-494-mediated TGIF1

Authors: Yang Yang, Yuan Zhang, Zongxiang Lin, Kai Wu, Zhanfeng He, Dengyan Zhu, Jia Zhao, Chunyang Zhang, Yuxia Fan

Published in: Cancer Cell International | Issue 1/2022

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Abstract

Background

Deacetylation of histones by histone deacetylase 3 (HDAC3) acts importantly in modulating apoptosis, DNA damage and cellular progression. Herein, we aimed to unravel the functional role of HDAC3 in a lethal disease, esophageal squamous cell carcinoma (ESCC).

Methods

The expression of HDAC3 in clinically collected ESCC tissues was determined by RT-qPCR and immunohistochemistry. As revealed from bioinformatics analysis, the putative relations between HDAC3 and microRNA-494 (miR-494) and between miR-494 and transforming growth factor beta (TGFβ)-inducing factor 1 (TGIF1) were further verified by chromatin immunoprecipitation and dual-luciferase reporter gene assay. Functional roles of shRNA-mediated depletion of HDAC3, miR-494 mimic and overexpressed TGIF1 were explored by gain- and loss-of-function assays with regard to ESCC cell biological behaviors. A nude mouse model of ESCC was developed for in vivo validation.

Results

HDAC3 was highly expressed in ESCC tissues, suggestive of poor prognosis while TGIF1 was upregulated and miR-494 was downregulated. Mechanistic investigation revealed that HDAC3 inhibited miR-494 expression and TGIF1 was a direct target of miR-494. Furthermore, silencing HDAC3 or overexpressing miR-494 was demonstrated to suppress aggressive phenotypes of ESCC cells both in vitro through the activated TGFβ signaling pathway and in vivo, while TGIF1 overexpression induced opposite results.

Conclusion

Collectively, our findings provided demonstration regarding the oncogenic property of HDAC3 in ESCC via the miR-494/TGIF1/TGFβ axis.
Appendix
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Literature
1.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.PubMedCrossRef
2.
Lam AK. Introduction: esophageal squamous cell carcinoma-current status and future advances. Methods Mol Biol. 2020;2129:1–6.PubMedCrossRef
3.
4.
Reichenbach ZW, Murray MG, Saxena R, Farkas D, Karassik EG, Klochkova A, et al. Clinical and translational advances in esophageal squamous cell carcinoma. Adv Cancer Res. 2019;144:95–135.PubMedCrossRef
5.
6.
7.
mcclure JJ, Li X, Chou CJ. Advances and challenges of HDAC inhibitors in cancer therapeutics. Adv Cancer Res. 2018;138:183–211.PubMedCrossRef
8.
Cao F, Zwinderman MRH, Dekker FJ. The process and strategy for developing selective histone deacetylase 3 inhibitors. Molecules. 2018;23:551.PubMedCentralCrossRef
9.
Zhang L, Chen Y, Jiang Q, Song W, Zhang L. Therapeutic potential of selective histone deacetylase 3 inhibition. Eur J Med Chem. 2019;162:534–42.PubMedCrossRef
10.
Adhikari N, Amin SA, Trivedi P, Jha T, Ghosh B. HDAC3 is a potential validated target for cancer: an overview on the benzamide-based selective HDAC3 inhibitors through comparative SAR/QSAR/QAAR approaches. Eur J Med Chem. 2018;157:1127–42.PubMedCrossRef
11.
Koumangoye RB, Andl T, Taubenslag KJ, Zilberman ST, Taylor CJ, Loomans HA, et al. SOX4 interacts with EZH2 and HDAC3 to suppress microRNA-31 in invasive esophageal cancer cells. Mol Cancer. 2015;14:24.PubMedPubMedCentralCrossRef
12.
Wang Y, Frank DB, Morley MP, Zhou S, Wang X, Lu MM, et al. HDAC3-dependent epigenetic pathway controls lung alveolar epithelial cell remodeling and spreading via miR-17-92 and TGF-beta signaling regulation. Dev Cell. 2016;36:303–15.PubMedPubMedCentralCrossRef
13.
Zhang R, Chen X, Zhang S, Zhang X, Li T, Liu Z, et al. Upregulation of miR-494 inhibits cell growth and invasion and induces cell apoptosis by targeting cleft lip and palate transmembrane 1-like in esophageal squamous cell carcinoma. Dig Dis Sci. 2015;60:1247–55.PubMedCrossRef
14.
15.
Chen X, Xie D, Zhao Q, You ZH. MicroRNAs and complex diseases: from experimental results to computational models. Brief Bioinform. 2019;20:515–39.PubMedCrossRef
16.
Jiang YY, Lin DC, Mayakonda A, Hazawa M, Ding LW, Chien WW, et al. Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma. Gut. 2017;66:1358–68.PubMedCrossRef
17.
Guca E, Sunol D, Ruiz L, Konkol A, Cordero J, Torner C, et al. TGIF1 homeodomain interacts with Smad MH1 domain and represses TGF-beta signaling. Nucleic Acids Res. 2018;46:9220–35.PubMedPubMedCentralCrossRef
18.
Nishimura T, Tamaoki M, Komatsuzaki R, Oue N, Taniguchi H, Komatsu M, et al. SIX1 maintains tumor basal cells via transforming growth factor-beta pathway and associates with poor prognosis in esophageal cancer. Cancer Sci. 2017;108:216–25.PubMedPubMedCentralCrossRef
19.
Singh V, Singh AP, Sharma I, Singh LC, Sharma J, Borthakar BB, et al. Epigenetic deregulations of Wnt/beta-catenin and transforming growth factor beta-Smad pathways in esophageal cancer: outcome of DNA methylation. J Cancer Res Ther. 2019;15:192–203.PubMed
20.
21.
Cheng R, Chen Y, Zhou H, Wang B, Du Q, Chen Y. B7–H3 expression and its correlation with clinicopathologic features, angiogenesis, and prognosis in intrahepatic cholangiocarcinoma. APMIS. 2018;126:396–402.PubMedCrossRef
22.
Hamid AA, Hasanain M, Singh A, Bhukya B, Omprakash, Vasudev PG, et al. Synthesis of novel anticancer agents through opening of spiroacetal ring of diosgenin. Steroids. 2014;87:108–18.
23.
Hamid AA, Kaushal T, Ashraf R, Singh A, Chand Gupta A, Prakash O, et al. (22beta,25R)-3beta-Hydroxy-spirost-5-en-7-iminoxy-heptanoic acid exhibits anti-prostate cancer activity through caspase pathway. Steroids. 2017;119:43–52.PubMedCrossRef
24.
Liu Y, Gao L, Zhao X, Guo S, Liu Y, Li R, et al. Saikosaponin A protects from pressure overload-induced cardiac fibrosis via inhibiting fibroblast activation or endothelial cell EndMT. Int J Biol Sci. 2018;14(13):1923–34.PubMedPubMedCentralCrossRef
25.
Wang PL, Liu B, Xia Y, Pan CF, Ma T, Chen YJ. Long non-coding RNA-low expression in tumor inhibits the invasion and metastasis of esophageal squamous cell carcinoma by regulating p53 expression. Mol Med Rep. 2016;13(4):3074–82.PubMedPubMedCentralCrossRef
26.
Diaz D, Prieto A, Reyes E, Barcenilla H, Monserrat J, Alvarez-Mon M. Flow cytometry enumeration of apoptotic cancer cells by apoptotic rate. Methods Mol Biol. 2015;1219:11–20.PubMedCrossRef
27.
Srivastava A, Fatima K, Fatima E, Singh A, Singh A, Shukla A, et al. Fluorinated benzylidene indanone exhibits antiproliferative activity through modulation of microtubule dynamics and antiangiogenic activity. Eur J Pharm Sci. 2020;154:105513.PubMedCrossRef
28.
Ju Q, Jiang M, Huang W, Yang Q, Luo Z, Shi H. CtBP2 interacts with TGIF to promote the progression of esophageal squamous cell cancer through the Wnt/betacatenin pathway. Oncol Rep. 2022;47(2):1–13.
29.
30.
Xiong G, Diao D, Lu D, Liu X, Liu Z, Mai S, et al. Circular RNA circNELL2 acts as the sponge of miR-127-5p to promote esophageal squamous cell carcinoma progression. Onco Targets Ther. 2020;13:9245–55.PubMedPubMedCentralCrossRef
31.
Su C, Liu W, Jiang T, Liu J. miR-488-5p promotes esophageal squamous cell carcinoma progression by suppressing the P53 pathway. J Thorac Dis. 2021;13(9):5534–45.PubMedPubMedCentralCrossRef
32.
Zhang L, Ma J, Han Y, Liu J, Zhou W, Hong L, et al. Targeted therapy in esophageal cancer. Expert Rev Gastroenterol Hepatol. 2016;10:595–604.PubMedCrossRef
33.
Qin S, Xu C, Li S, Yang C, Sun X, Wang X, et al. Indomethacin induces apoptosis in the EC109 esophageal cancer cell line by releasing second mitochondria-derived activator of caspase and activating caspase-3. Mol Med Rep. 2015;11:4694–700.PubMedCrossRef
34.
Mroczko B, Kozlowski M, Groblewska M, Lukaszewicz M, Niklinski J, Jelski W, et al. The diagnostic value of the measurement of matrix metalloproteinase 9 (MMP-9), squamous cell cancer antigen (SCC) and carcinoembryonic antigen (CEA) in the sera of esophageal cancer patients. Clin Chim Acta. 2008;389:61–6.PubMedCrossRef
35.
Chen X, Liu M, Meng F, Sun B, Jin X, Jia C. The long noncoding RNA HIF1A-AS2 facilitates cisplatin resistance in bladder cancer. J Cell Biochem. 2019;120:243–52.PubMedCrossRef
36.
Guo XQ, Li XY. The expression and clinical significance of metastasis suppressor gene and matrix metalloproteinase-2 in esophageal squamous cell of carcinoma. Pak J Pharm Sci. 2016;29:1339–42.PubMed
37.
Liu X, Wang JH, Li S, Li LL, Huang M, Zhang YH, et al. Histone deacetylase 3 expression correlates with vasculogenic mimicry through the phosphoinositide3-kinase / ERK-MMP-laminin5gamma2 signaling pathway. Cancer Sci. 2015;106:857–66.PubMedPubMedCentralCrossRef
38.
Zhang L, Hong Z, Zhang RR, Sun XZ, Yuan YF, Hu J, et al. Bakkenolide A inhibits leukemia by regulation of HDAC3 and PI3K/Akt-related signaling pathways. Biomed Pharmacother. 2016;83:958–66.PubMedCrossRef
39.
Zhao H, Li G, Zhang S, Li F, Wang R, Tao Z, et al. Inhibition of histone deacetylase 3 by MiR-494 alleviates neuronal loss and improves neurological recovery in experimental stroke. J Cereb Blood Flow Metab. 2019;39:2392–405.PubMedPubMedCentralCrossRef
40.
Chen Z, Hu X, Wu Y, Cong L, He X, Lu J, et al. Long non-coding RNA XIST promotes the development of esophageal cancer by sponging miR-494 to regulate CDK6 expression. Biomed Pharmacother. 2019;109:2228–36.PubMedCrossRef
41.
42.
Ali Syeda Z, Langden SSS, Munkhzul C, Lee M, Song SJ. Regulatory mechanism of microRNA expression in cancer. Int J Mol Sci. 2020;21:1723.PubMedCentralCrossRef
43.
Xiang G, Yi Y, Weiwei H, Weiming W. TGIF1 promoted the growth and migration of cancer cells in nonsmall cell lung cancer. Tumour Biol. 2015;36:9303–10.PubMedCrossRef
44.
Pu Y, Xiang J, Zhang J. KDM5B-mediated microRNA-448 up-regulation restrains papillary thyroid cancer cell progression and slows down tumor growth via TGIF1 repression. Life Sci. 2020;250:117519.PubMedCrossRef
45.
Parajuli P, Singh P, Wang Z, Li L, Eragamreddi S, Ozkan S, et al. TGIF1 functions as a tumor suppressor in pancreatic ductal adenocarcinoma. EMBO J. 2019;38:e101067.PubMedPubMedCentralCrossRef
46.
Neuzillet C, Tijeras-Raballand A, Cohen R, Cros J, Faivre S, Raymond E, et al. Targeting the TGFbeta pathway for cancer therapy. Pharmacol Ther. 2015;147:22–31.PubMedCrossRef
47.
Wu L, Herman JG, Brock MV, Wu K, Mao G, Yan W, et al. Silencing DACH1 promotes esophageal cancer growth by inhibiting TGF-beta signaling. PLoS ONE. 2014;9:e95509.PubMedPubMedCentralCrossRef
48.
Liu Y, Lai L, Chen Q, Song Y, Xu S, Ma F, et al. MicroRNA-494 is required for the accumulation and functions of tumor-expanded myeloid-derived suppressor cells via targeting of PTEN. J Immunol. 2012;188:5500–10.PubMedCrossRef
49.
Gu LZ, Sun H, Chen JH. Histone deacetylases 3 deletion restrains PM2.5-induced mice lung injury by regulating NF-kappaB and TGF-beta/Smad2/3 signaling pathways. Biomed Pharmacother. 2017;85:756–62.PubMedCrossRef
Metadata
Title
Silencing of histone deacetylase 3 suppresses the development of esophageal squamous cell carcinoma through regulation of miR-494-mediated TGIF1
Authors
Yang Yang
Yuan Zhang
Zongxiang Lin
Kai Wu
Zhanfeng He
Dengyan Zhu
Jia Zhao
Chunyang Zhang
Yuxia Fan
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2022
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-022-02581-3

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