HDAC9 Is Preferentially Expressed in Dedifferentiated Hepatocellular Carcinoma Cells and Is Involved in an Anchorage-Independent Growth

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2020 Sep 26

PMID 32977608

Citations 8

Authors

Keita Kanki

Ryota Watanabe

Le Nguyen Thai

Chun-Hao Zhao

Kyoko Naito

Affiliations

Soon will be listed here.

Abstract

Aberrant activation of histone deacetylases (HDACs) is one of the causes of tumor cell transformation in many types of cancer, however, the critical HDAC responsible for the malignant transformation remain unclear. To identify the HDAC related to the dedifferentiation of hepatocellular carcinoma (HCC) cells, we investigated the expression profile of HDACs in differentiated and undifferentiated hepatoma cells. We found that HDAC9, a member of the class II HDAC, is preferentially expressed in undifferentiated HCC cells. Analysis of 373 HCC patients in The Cancer Genome Atlas (TCGA) database revealed that the expression of HDAC9 mRNA positively correlated with the markers of mesenchymal phenotype and stemness, and conversely, negatively correlated with hepatic differentiation markers. HDAC9 was transcriptionally upregulated in epithelial-mesenchymal transition (EMT)-induced HCC cells treated with TGF-β. Genetic and pharmacological inhibition of HDAC9 in undifferentiated HCC cells showed decreased sphere-forming activity, which indicates an ability of anchorage-independent cell growth and self-renewal. We also showed that aldehyde dehydrogenase 1A3 (ALDH1A3) was downregulated in HDAC9-suppressing cells, and ALDH inhibitor disulfiram significantly decreased the sphere formation of undifferentiated HCC cells. Together, our data provide useful information for the development of HDAC9-specific inhibitors for the treatment of HCC progression.

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References

Hao Y, Baker D, Ten Dijke P . TGF-β-Mediated Epithelial-Mesenchymal Transition and Cancer Metastasis. Int J Mol Sci. 2019; 20(11). PMC: 6600375. DOI: 10.3390/ijms20112767. View

Flores-Tellez T, Villa-Trevino S, Pina-Vazquez C . Road to stemness in hepatocellular carcinoma. World J Gastroenterol. 2017; 23(37):6750-6776. PMC: 5645611. DOI: 10.3748/wjg.v23.i37.6750. View

Csordas A . On the biological role of histone acetylation. Biochem J. 1990; 265(1):23-38. PMC: 1136610. DOI: 10.1042/bj2650023. View

Chen S, Yin C, Lao T, Liang D, He D, Wang C . AMPK-HDAC5 pathway facilitates nuclear accumulation of HIF-1α and functional activation of HIF-1 by deacetylating Hsp70 in the cytosol. Cell Cycle. 2015; 14(15):2520-36. PMC: 4614078. DOI: 10.1080/15384101.2015.1055426. View

Yang J, Hainaut P, Gores G, Amadou A, Plymoth A, Roberts L . A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019; 16(10):589-604. PMC: 6813818. DOI: 10.1038/s41575-019-0186-y. View

Zhao D, Mo Y, Li M, Zou S, Cheng Z, Sun Y . NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells. J Clin Invest. 2014; 124(12):5453-65. PMC: 4348941. DOI: 10.1172/JCI76611. View

Huang Y, Jian W, Zhao J, Wang G . Overexpression of is associated with poor prognosis and tumor progression of breast cancer in Chinese females. Onco Targets Ther. 2018; 11:2177-2184. PMC: 5909784. DOI: 10.2147/OTT.S164583. View

Chen M, Weng J, Cheng C, Wu R, Huang S, Wu C . ALDH1A3, the Major Aldehyde Dehydrogenase Isoform in Human Cholangiocarcinoma Cells, Affects Prognosis and Gemcitabine Resistance in Cholangiocarcinoma Patients. Clin Cancer Res. 2016; 22(16):4225-35. DOI: 10.1158/1078-0432.CCR-15-1800. View

Barneda-Zahonero B, Parra M . Histone deacetylases and cancer. Mol Oncol. 2012; 6(6):579-89. PMC: 5528343. DOI: 10.1016/j.molonc.2012.07.003. View

10.

Subramanian S, Bates S, Wright J, Espinoza-Delgado I, Piekarz R . Clinical Toxicities of Histone Deacetylase Inhibitors. Pharmaceuticals (Basel). 2016; 3(9):2751-2767. PMC: 4034096. DOI: 10.3390/ph3092751. View

11.

Yuan Z, Peng L, Radhakrishnan R, Seto E . Histone deacetylase 9 (HDAC9) regulates the functions of the ATDC (TRIM29) protein. J Biol Chem. 2010; 285(50):39329-38. PMC: 2998079. DOI: 10.1074/jbc.M110.179333. View

12.

Rodriguez-Torres M, Allan A . Aldehyde dehydrogenase as a marker and functional mediator of metastasis in solid tumors. Clin Exp Metastasis. 2015; 33(1):97-113. PMC: 4740561. DOI: 10.1007/s10585-015-9755-9. View

13.

Mima K, Okabe H, Ishimoto T, Hayashi H, Nakagawa S, Kuroki H . CD44s regulates the TGF-β-mediated mesenchymal phenotype and is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Res. 2012; 72(13):3414-23. DOI: 10.1158/0008-5472.CAN-12-0299. View

14.

Hu Y, Sun L, Tao S, Dai M, Wang Y, Li Y . Clinical significance of HDAC9 in hepatocellular carcinoma. Cell Mol Biol (Noisy-le-grand). 2019; 65(4):23-28. View

15.

Lee Y, Seo D, Choi K, Andersen J, Won M, Kitade M . Antitumor effects in hepatocarcinoma of isoform-selective inhibition of HDAC2. Cancer Res. 2014; 74(17):4752-61. PMC: 4155016. DOI: 10.1158/0008-5472.CAN-13-3531. View

16.

Li H, Li X, Lin H, Gong J . High HDAC9 is associated with poor prognosis and promotes malignant progression in pancreatic ductal adenocarcinoma. Mol Med Rep. 2020; 21(2):822-832. PMC: 6947911. DOI: 10.3892/mmr.2019.10869. View

17.

Gore J, Craven K, Wilson J, Cote G, Cheng M, Nguyen H . TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis. Oncotarget. 2015; 6(10):7504-21. PMC: 4480696. DOI: 10.18632/oncotarget.3233. View

18.

Liang Z, Feng A, Shim H . MicroRNA-30c-regulated HDAC9 mediates chemoresistance of breast cancer. Cancer Chemother Pharmacol. 2020; 85(2):413-423. DOI: 10.1007/s00280-019-04024-9. View

19.

Marcato P, Dean C, Pan D, Araslanova R, Gillis M, Joshi M . Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform ALDH1A3 and its expression is predictive of metastasis. Stem Cells. 2011; 29(1):32-45. DOI: 10.1002/stem.563. View

20.

Ler S, Leung C, Khin L, Lu G, Salto-Tellez M, Hartman M . HDAC1 and HDAC2 independently predict mortality in hepatocellular carcinoma by a competing risk regression model in a Southeast Asian population. Oncol Rep. 2015; 34(5):2238-50. PMC: 4583520. DOI: 10.3892/or.2015.4263. View