title: 1,25(OH)2D3 inhibits the progression of hepatocellular carcinoma via downregulating HDAC2 and upregulating P21(WAFI/CIP1).
abstract: Vitamin D, termed 1,25(OH)2D3 in it's active form, activity is associated with a reduced risk of hepatocellular carcinoma (HCC) and is an important immune regulator. However, the detail molecular mechanisms underlying the effects of 1,25(OH)2D3 on the progression of HCC are widely unknown. Histone deacetwylase 2 (HDAC2) is usually expressed at high levels in tumors, and its downregulation leads to high expression levels of cell cycle components, including p21(WAF1/Cip1), a well-characterized modulator, which is critical in cell senescence and apoptosis. The present study investigated whether vitamin D inhibits HCC via the regulation of HDAC2 and p21(WAF1/Cip1). Firstly, the toxic concentrations of 1,25(OH)2D3 were determined, according to trypan blue and [(3)H]thymidine incorporation assays. Secondly, HCC cells lines were treated with different concentrations of 1,25(OH)2D3. The expression of HDAC2 was either silenced via short hairpin (sh)RNA or induced by transfection of plasmids expressing the HDAC2 gene in certain HCC cells. Finally the mRNA and protein levels of HDAC2 and p21(WAF1/Cip1) were measured using reverse transcription-quantitative polymerase chain reaction and western blot analyses. The results revealed that 1,25(OH)2D3 treatment reduced the expression of HDAC2 and increased the expression of p21(WAF1/Cip1), in a dose-dependent manner, resulting in the reduction of HCC growth. Elevated levels of HDAC2 reduced the expression of p21(WAF1/Cip1), resulting in an increase in HCC growth. HDAC2 shRNA increased the expression of p21(WAF1/Cip1), resulting in reduction in HCC growth. Thus, 1,25(OH)2D3 exerted antitumorigenic effects through decreasing the expression levels of HDAC2 and increasing the expression of p21(WAF1/Cip1), which inhibited the development of HCC and may indicate the possible underlying mechanism. These results suggest that vitamin D3 may be developed as a potential drug for effective therapy in the treatment of HCC.
authors.affiliation: Biochemistry Department, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: Medical Laboratory, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China.
authors.forename: Guozhen
authors.initials: G
authors.lastname: Yang
authors.affiliation: Biochemistry Department, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China.
authors.forename: Yunzhu
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Biochemistry Department, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China.
authors.forename: Weiying
authors.initials: W
authors.lastname: Kong
authors.affiliation: Medical Laboratory, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
mesh_terms: D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002762:Cholecalciferol / Q000494:pharmacology / Q000627:therapeutic use*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger; D002762:Cholecalciferol