title: MicroRNA-221 governs tumor suppressor HDAC6 to potentiate malignant progression of liver cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Hyun Jin
authors: HJ
authors: Bae
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Kwang Hwa
authors: KH
authors: Jung
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Jung Woo
authors: JW
authors: Eun
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Qingyu
authors: Q
authors: Shen
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Hyung Seok
authors: HS
authors: Kim
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Se Jin
authors: SJ
authors: Park
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Woo Chan
authors: WC
authors: Shin
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Hee Doo
authors: HD
authors: Yang
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Won Sang
authors: WS
authors: Park
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Jung Young
authors: JY
authors: Lee
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Cancer Evolution Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea. Electronic address: swnam@catholic.ac.kr.
authors: Suk Woo
authors: SW
authors: Nam
mesh_terms: D000818:Animals; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000235:genetics*; D051381:Rats
chemical_list: C546122:MIRN221 microRNA, mouse; D035683:MicroRNAs; D012334:RNA, Neoplasm; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: Histone deacetylase 6; JNK/c-Jun; Liver cancer; MicroRNA-221; NF-κB