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KDM6A suppresses hepatocellular carcinoma cell proliferation by negatively regulating the TGF-?/SMAD signaling pathway.

ABSTRACT: Lysine demethylase 6A (KDM6A) is a Jumonji-C domain-containing histone demethylase that specifically catalyzes the removal of histone H3 lysine-27 trimethylation. KDM6A is a member of the KDM6 family, the biological role of which has been reported in various types of cancer, including bladder and lung cancer, as well as pancreatic ductal adenocarcinoma. However, the role of KDM6A in hepatocellular carcinoma (HCC) is not completely understood. Therefore, the present study aimed to determine the biological function of KDM6A in HCC progression. The expression profile of KDM6A was examined in HCC surgical specimens using reverse transcription-quantitative PCR. In addition, the role of KDM6A in the proliferation capacities of HCC cell lines was examined in vitro and in vivo using crystal violet and MTT assays. The underlying mechanism by which KDM6A exerts its function was explored by western blotting. The present study indicated that KDM6A was significantly downregulated in HCC tissues compared with normal control tissues. The role of KDM6A in HCC cell proliferation was also determined. KDM6A overexpression significantly inhibited HCC cell proliferation, whereas KDM6A knockdown significantly promoted HCC cell proliferation compared with the corresponding control groups. Consistently, KDM6A overexpression suppressed HCC cell tumorigenesis in vivo. The western blotting results indicated that KDM6A overexpression decreased the phosphorylation levels of smad2, whereas KDM6A knockdown increased the phosphorylation levels of smad2 compared with the corresponding control groups. Therefore, the present study suggested that KDM6A may inhibit HCC cell proliferation by negatively regulating the TGF-?/SMAD signaling pathway, suggesting that KDM6A may serve as a potential target for the diagnosis and treatment of HCC.

SUBMITTER: Li Y

PROVIDER: S-EPMC7401926 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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KDM6A suppresses hepatocellular carcinoma cell proliferation by negatively regulating the TGF-β/SMAD signaling pathway.

Li Yuan Y Yang Jing J Zhang Xin X Liu Hong H Guo Jin J

Experimental and therapeutic medicine 20200713 3

Lysine demethylase 6A (KDM6A) is a Jumonji-C domain-containing histone demethylase that specifically catalyzes the removal of histone H3 lysine-27 trimethylation. KDM6A is a member of the KDM6 family, the biological role of which has been reported in various types of cancer, including bladder and lung cancer, as well as pancreatic ductal adenocarcinoma. However, the role of KDM6A in hepatocellular carcinoma (HCC) is not completely understood. Therefore, the present study aimed to determine the b ...[more]

PMID: 32765772

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Project description:Berberine (BBR), a natural alkaloid derived from Coptis, has anticancer activity. Some researchers have found that it could restrain epithelial-mesenchymal transition (EMT) of melanoma, neuroblastoma, and other tumor cells. However, it is unclear whether BBR can reverse EMT in hepatocellular carcinoma (HCC) and gastric carcinoma (GC). In our study, BBR inhibited the migration and invasion of HepG2, MGC803, and SGC7901 cells in a dose-dependent manner. Transcription sequencing assays showed that Vimentin, MMP, and Smad3 were downregulated, but Smad2, Smad6, TAB2, ZO-1, and claudin 7 were upregulated when treated with BBR. GO Enrichment analysis of KEGG pathway showed that BBR significantly inhibited TGF-β/Smad at 12 h, then, PI3K/Akt and Wnt/β-catenin signaling pathways at 24 h, which were closely related to the proliferation, migration, and EMT. The results of the transcriptome sequencing analysis were verified by Western Blot. It showed that the expression of epithelial marker E-cadherin and ZO-1 remarkably augmented with BBR treatment, as well as declined mesenchymal markers, including N-cadherin and Vimentin, decreased transcription factor Snail and Slug. The effects of BBR were similar to those of the PI3K inhibitor LY294002 and TGF-β receptor inhibitor SB431542. Furthermore, β-catenin and phosphorylation of AKT, Smad2, and Smad3 were changed dose-dependently by BBR treatment, which upregulated p-Smad2 and downregulated the others. Combined with LY or SB, respectively, BBR could enhance the effects of the two inhibitors. Simultaneously, IGF-1 and TGF-β, which is the activator of PI3K/AKT and TGF-β/Smad, respectively, could reverse the anti-EMT effect of BBR. The Molecular Docking results showed BBR had a high affinity with the TGF-β receptor I (TGFβR1), and the binding energy was -7.5 kcal/mol, which is better than the original ligand of TGFβR1. Although the affinity of BBR with TGF-β receptor II (TGFβR2) was lower than the original ligand of TGFβR2, the more considerable negative binding energy (-8.54 kcal/mol) was obtained. BBR upregulated p-Smad2, which was different from other reports, indicating that the function of Smad2 was relatively complex. Combination BBR with SB could enhance the effect of the inhibitor on EMT, and the results indicated that BBR binding to TGFβR was not competitive with SB to TGFβR since different binding amino acid sites. Our experiments demonstrated BBR increased p-Smad2 and decreased p-Smad3 by binding to TGFβR1 and TGβFR2 inhibiting TGF-β/Smad, then, PI3K/AKT and other signaling pathways to restrain EMT, metastasis, and invasion in tumor cells. The effect of BBR was similar on the three tumor cells.

Project description:Renal fibrosis denotes a common complication of diabetic nephropathy and is a predominant cause of end-stage renal disease. Despite the association between microRNAs (miRNAs or miRs) and renal fibrosis, miRNAs have been reported to play a vital role in the development of chronic renal fibrosis. Therefore, the aim of the present study was to investigate the possible function of miR-101a in chronic renal fibrosis. Initially, microarray-based gene expression profiling of renal fibrosis was employed to screen the differentially expressed genes. An in vivo mouse model of chronic renal fibrosis induced by a unilateral ureteral obstruction (UUO) and an in vitro cell model induced by aristolochic acid (AA) were constructed. miR-101a expression was examined using a fluorescence in situ hybridization (FISH) assay and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Then, the interaction between miR-101a and KDM3A was identified using an online website combined with a dual-luciferase reporter assay. Finally, gain- and loss-of-function experiments were conducted to elucidate the effect of miR-101a on the expression of Col1a1, fibronectin, ?-smooth muscle actin (?-SMA), and YAP-TGF-? (transforming growth factor ?)-Smad signaling pathway-related genes, as well as the degree of renal fibrosis. miR-101a was poorly expressed while KDM3A was robustly induced in chronic renal fibrosis tissues and cells. In addition, miR-101a could target and downregulate KDM3A expression, which led to elevated TGIF1, inhibited expression of Collagen I (Col1a1), fibronectin, ?-SMA, YAP1, and TGF-?2 along with the extent of Smad2/3 phosphorylation, as well as delayed renal fibrosis degree. Besides, overexpressed YAP/TGF-?2 or inhibited TGIF1 partially restored the inhibitory effect of miR-101a on chronic renal fibrosis. Taken together, miR-101a could potentially slow down chronic renal fibrosis by the inactivation of the YAP-TGF-?-Smad signaling pathway via KDM3A, highlighting the potential of miR-101a as a therapeutic target for chronic renal fibrosis treatment.

Dataset Information

KDM6A suppresses hepatocellular carcinoma cell proliferation by negatively regulating the TGF-?/SMAD signaling pathway.

Publications

KDM6A suppresses hepatocellular carcinoma cell proliferation by negatively regulating the TGF-β/SMAD signaling pathway.

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