Understanding The Role Of HDAC7 In Colon Cancer LS174T Cell Line

Epigenetic transcription regulators precisely control multi-levels of covalent chemical modification at chromatin,to sustain the equilibrium and order of gene transcription and ensure proper cell differentiation and development.However,aberrant expression of these regulators often leads to irregular chromatin modification and gene transcription,consequently resulting in a variety of human cancers and chronic inflammation diseases.Therefore,it is fundamental to clarify the functional role of epigenetic regulators in gene transcription regulation and understand their driving mechanism for the development of innovative targeted drugs in diseases.Post-translational covalent modification of histone closely associates with proper gene expression,and is one of the important forms of epigenetic regulation,including methylation,acetylation and phosphorylation.Abnormal levels of these modifications play important roles in the development of various malignancies.Histone acetylation by histone acetylation transferase（HAT）transfers the acetylation group to histone lysine residue and activates gene transcription,whereas histone deacetylation enzyme（HDAC）to removes the acetylation group from histone lysine reside and inhibits gene transcription.HAT and HDAC work together to dynamically and reversibly control the acetylation level of histones in distinct gene loci at chromatin and regulate gene transcriptional activity.HDAC protein family are epigenetic transcription regulators.It can be divided into four classes: Class I consists of HDAC1,2,3 and 8,Class II has two subtypes: Class IIa includes HDAC4,5,7,9;Class IIb HDAC6 and 10 proteins;Class III group contains Sirt1,2,3,4,5,6 and7 proteins;HDAC11 is the only protein in the Class IV.HDAC7,a member of the Class IIa family of histone deacetylases,does not directly recognize DNA but rather binds to transcription factors and occupies at specific gene regions.Previous studies have shown that HDAC7 is specifically associated with cellular differentiation,morphological development,vascular remodeling,and B cell and T cell development.HDAC7 is overexpressed in many cancers,including colon cancer and correlates with poor patient prognosis for various malignancies,therefore has been considered as a potential therapeutic drug target.However,its functional mechanism in tumor driving is still insufficiently understood.Colon cancer is a common malignant tumor originating in colonic mucosa epithelium.In recent years,the incidence of colon cancer is increasing year by year in China.The etiology of colonic cancer is complicated,and the cause of formation is not completely clear.The current treatment of colon cancer is primarily a multidisciplinary treatment strategy and comprehensively relies on surgery,radiotherapy,chemotherapy,immunotherapy,traditional Chinese medicine and other treatments.However,in China,more than 50% of colorectal cancer patients missed the best time for diagnosis and treatment because cancer was found in the advanced stage,resulting in poor long-term prognosis and low 5-year survival rate.Therefore,it is necessary to explore new therapeutic drugs and markers for colorectal cancer for prognosis prediction.In this study,we explored the mechanism of HDAC7 protein in colon cancer.We constructed LS174 T cell line with stable knockdown of HDAC7 by sh RNA,and found that HDAC7 knockdown increased the expression of ATF3,and enhanced the p-AKT and P21 protein levels,leading to lower AKT signaling pathway activity,the suppression of cell proliferation and stimulation of cell apoptosis.Furthermore,ectopic expression of HDAC7 in the HDAC7 knockdown LS174T cells improved the cell proliferation and reduced apoptosis.These results suggest that HDAC7 plays an important role in cell proliferation and apoptosis in colon cancer cells.In addition,we added histone deacetylase（HDAC）inhibitor SAHA or Class IIa inhibitor TMP269 in LS174 T cells,and found that these inhibitors inhibited cell proliferation and promoted cell apoptosis of LS174 T cells,further validated the key role of HDAC7 in cell cycle arrest and apoptosis of colon cancer cells.These data illustrate that HDAC7 can be used as a potential drug target for the treatment of colon cancer.