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Hypermethylated KCNQ1 acts as a tumor suppressor in hepatocellular carcinoma

Author:
Fan, Haiyan, Zhang, Meng, Liu, Wei
Source:
Biochemical and biophysical research communications 2018 v.503 no.4 pp. 3100-3107
ISSN:
0006-291X
Subject:
DNA, Western blotting, apoptosis, beta catenin, bioinformatics, cell lines, gain-of-function mutation, gene expression regulation, hepatoma, metastasis, neoplasm cells, patients, phenotype, potassium channels, prognosis, quantitative polymerase chain reaction, therapeutics, tissues
Abstract:
Potassium (K⁺) channels are dysregulated in tumor tissues and functionally these channels contribute significantly to the malignant phenotypes of the cancer cells, including cell apoptosis, chemo- and radio-resistance, proliferation, and migration. However, little is known about the potential implications of K⁺ channels in hepatocellular carcinoma (HCC). The aim of the current study was to investigate the expression profile of KCNQ1 in HCC and assess its possible cellular implications as well as mechanism to disease progression. Using real-time qPCR and western blotting technique, we found that KCNQ1 was frequently down-regulated in HCC cell lines and tissues, and HCC patients with lower KCNQ1 expression had a poor prognosis. Specifically, DNA hypermethylation of KCNQ1 promoter resulted in its downregulation in HCC. Bioinformatic analysis indicated a regulatory role of KCNQ1 in the epithelial-to-mesenchymal transition process. Gain-of-function study showed that KCNQ1 exhibited remarkable inhibitory roles on tumor metastasis in vitro and in vivo. Mechanistically, KCNQ1 can interact with β-catenin to affect its subcellular distribution and subsequently reduce the activity of Wnt/β-catenin signaling, which further blocks the expression of its downstream targets, including c-Myc, MMP7, and CCND1. Restoration of β-catenin activity largely compromised the tumor-suppressive roles of KCNQ1 in the invasive capacity of HCC cells. In conclusion, KCNQ1 is down-regulated in HCC and may suppress HCC metastasis, which could represent a prognostic marker and promising therapeutic target for HCC.
Agid:
6129152