Abstract 3111: JNK/c-Jun- and NF-κB-mediated microRNA-221 governs tumor suppressor HDAC6 to potentiate malignant progression of liver cancer

Abstract

Abstract Many clinical studies of cancer patients have established that the most common reason behind changes in HDAC function is its overexpression. However, among HDACs in liver cancer, HDAC6, a cytoplasmic tubulin deacetylase, is uniquely endowed with a tumor suppressor, but the mechanism underlying HDAC6 inactivation has yet to be uncovered. In this study we show that genetic and epigenetic dysregulation was not part of the HDAC6 inactivation mechanism. Instead, microRNA-221-3p (miR-221) directly suppressed HDAC6 in hepatocellular carcinoma (HCC) cells. A comprehensive miRNA profiling analysis identified seven putative endogenous miRNAs that are significantly upregulated in HCC. Ectopic expression of miRNA mimics in Dicer knockdown cells evidenced miR-221 to suppress HDAC6 in HCC cells. Notably, targeted-disruption of miR-221 repressed cancer cell growth and proliferation, and it recapitulated HDAC6 overexpression effects in HCC cells. Our results also demonstrate that c-Met-mediated c-Jun NH2-terminal kinase (JNK)/c-Jun signaling induced miR-221 to suppress HDAC6 and was sustained in liver cancer cells but not in normal hepatic cells. In addition, cytokine-induced NF-κBp65 independently regulated miR-221, thereby suppressing HDAC6 expression in liver cancer cells. HCC tissues derived from chemical-induced rat liver cancer models validated that JNK/c-Jun activation and NF-kBp65 nuclear translocation are essential for the transcriptional activation of oncogenic miR-221 to repress tumor suppressor HDAC6 in HCC. In conclusion, our finding suggest that the functional loss or suppression of the tumor suppressor HDAC6 is caused by 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. Citation Format: Hyung Seok Kim, Qingyu Shen, Jung Woo Eun, Woo Chan Shin, Hee Doo Yang, Won Sang Park, Joung Young Lee, Suk Woo Nam. JNK/c-Jun- and NF-κB-mediated microRNA-221 governs tumor suppressor HDAC6 to potentiate malignant progression of liver cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3111. doi:10.1158/1538-7445.AM2015-3111