LncRNA HOTAIR epigenetically suppresses miR-122 expression in hepatocellular carcinoma via DNA methylation
Authors: Xiaoyu He
Guolin Li
Zhe Meng
Jiajia Zhou
Junge Deng
Rufu Chen
Di Cheng
Bin Zhang
Xiaogeng Deng
Huilin Ye
Lusheng Wei
Shangyou Zheng
Journal: EBioMedicine (2018)
Discipline: CLINICAL MEDICINE
Keywords: DNA methylation; Epigenetics; Hepatocellular carcinoma; LncRNA HOTAIR; microRNA-122.
Affiliations: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China; Department of Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China., Laboratory of Biomechanics and Physiology, Guangdong Provincial Institute of Sports Science, Guangzhou 510663, PR China., Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China., Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China; Department of Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China. Electronic address: .

Abstract:  Background: MicroRNA-122 (miR-122), a pivotal liver-specific miRNA, is frequently repressed in hepatocellular carcinoma (HCC) and associated with poor prognosis. Long non-coding RNA (lncRNA) HOTAIR has been proved to function as an oncogene in multiple cancers including HCC. However, the relationship between HOTAIR and miR-122 in HCC remains largely unknown. Methods: We investigated the function of HOTAIR and miR-122 in HCC cell models and a xenograft mouse model. The regulatory network between HOTAIR and miR-122 was further detected following overexpression or knockdown of HOTAIR. DNA methylation status of miR-122 promoter region, as well as expression levels of DNMTs, EZH2 and Cyclin G1 were analyzed. Findings: In this study, we found that HOTAIR was highly expressed whereas miR-122 was suppressed in HCC, and HOTAIR negatively regulated miR-122 expression in HCC cells. Furthermore, knockdown of HOTAIR dramatically inhibited HCC cell proliferation and induced cell cycle arrest in vitro and suppressed tumorigenicity in vivo by upregulating miR-122 expression. Mechanistically, a CpG island was located in the miR-122 promoter region. HOTAIR epigenetically suppressed miR-122 expression via DNMTs-mediated DNA methylation. Moreover, HOTAIR upregulated DNMTs expression via EZH2. In addition, suppression of miR-122 induced by HOTAIR directly reactivated oncogene Cyclin G1 expression. Collectively, our results suggest that HOTAIR epigenetically suppresses miR-122 expression via DNA methylation, leading to activation of Cyclin G1 and promotion of tumorigenicity in HCC, which provide new insight into the mechanism of HOTAIR-mediated hepatocarcinogenesis via suppressing miR-122. 

Retracted: No

PubPeer comments:
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 More western-blotting bands reuses can be found in **Fig. 7** (red box):   , 
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