MicroRNA-221 governs tumor suppressor HDAC6 to potentiate malignant progression of liver cancer.

Hyun Jin Bae, Kwang Hwa Jung, Jung Woo Eun, Qingyu Shen, Hyung Seok Kim, Se Jin Park, Woo Chan Shin, Hee Doo Yang, Won Sang Park, Jung Young Lee, Suk Woo Nam

Journal of hepatology 2015 Aug

filter terms:

Most common reason behind changes in histone deacetylase (HDAC) function is its overexpression in cancer. However, among HDACs in liver cancer, HDAC6 is uniquely endowed with a tumor suppressor, but the mechanism underlying HDAC6 inactivation has yet to be uncovered. Microarray profiling and target prediction programs were used to identify miRNAs targeting HDAC6. A series of inhibitors, activators and siRNAs was introduced to validate regulatory mechanisms for microRNA-221-3p (miR-221) governing HDAC6 in hepatocarcinogenesis. Comprehensive miRNA profiling analysis identified seven putative endogenous miRNAs that are significantly upregulated in hepatocellular carcinoma (HCC). While miR-221 was identified as a suppressor of HDAC6 by ectopic expression of miRNA mimics in Dicer knockdown cells, targeted-disruption of miR-221 repressed cancer cell growth through derepressing HDAC6 expression. Suppression of HDAC6 via miR-221 was induced by JNK/c-Jun signaling in liver cancer cells but not in normal hepatic cells. Additionally, cytokine-induced NF-κBp65 independently regulated miR-221, thereby suppressing HDAC6 expression in HCC cells. HCC tissues derived from chemical-induced rat and H-ras12V transgenic mice liver cancer models validated that JNK/c-Jun activation and NF-κBp65 nuclear translocation are essential for the transcription of miR-221 leading to repression of HDAC6 in HCC. Our findings suggest that the functional loss or suppression of the tumor suppressor HDAC6 is caused by induction of miR-221 through coordinated JNK/c-Jun- and NF-κB-signaling pathways during liver tumorigenesis, providing a novel target for the molecular treatment of liver malignancies. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Citation

Hyun Jin Bae, Kwang Hwa Jung, Jung Woo Eun, Qingyu Shen, Hyung Seok Kim, Se Jin Park, Woo Chan Shin, Hee Doo Yang, Won Sang Park, Jung Young Lee, Suk Woo Nam. MicroRNA-221 governs tumor suppressor HDAC6 to potentiate malignant progression of liver cancer. Journal of hepatology. 2015 Aug;63(2):408-19