LncRNA HOTAIR promotes human liver cancer stem cell malignant growth through downregulation of SETD2

// Haiyan Li 1 , Jiahui An 1 , Mengying Wu 1 , Qidi Zheng 1 , Xin Gui 1 , Tianming Li 1 , Hu Pu 1 , Dongdong Lu 1 1 School of Life Science and Technology, Tongji University, Shanghai 200092, China Correspondence to: Dongdong Lu, e-mail: ludongdong@tongji.edu.cn Keywords: lncRNA HOTAIR, liver cancer stem cell, SETD2, DNA mismatch repair, microsatellite instability Received: February 06, 2015 Accepted: June 19, 2015 Published: June 30, 2015 ABSTRACT Long non-coding RNA HOTAIR predicts negative tumor prognosis and exhibits oncogenic activity. Herein, we demonstrate HOTAIR promotes human liver cancer stem cell malignant growth through downregulation of SETD2. Mechanistically, HOTAIR reduces the recuritment of the CREB, P300, RNA polII onto the SETD2 promoter region that inhibits SETD2 expression and its phosphorylation. Thereby, the SETD2 binding capacity to substrate histone H3 is weakened, triggering a reduction of trimethylation on histone H3 thirty-sixth lysine, and thereby the H3K36me3–hMSH2-hMSH6-SKP2 complex is also decreased. Strikingly, the complex occupancy on chromosome is depressed, preventing from mismatch DNA repair. While reducing the degradation capacity of Skp 2 for aging histone H3 bound to damaged DNA, the aging histone repair is impaired. Furthermore, that the damaged DNA escaped to repair can causes microsatellite instability(MSI) and abnormal expression of cell cycle related genes that may trigger the hepatocarcinogenesis. This study provides evidence for HOTAIR to promote tumorigenesis via downregulating SETD2 in liver cancer stem cells.