Oncotarget

Research Papers:

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

Haiyan Li _, Jiahui An, Mengying Wu, Qidi Zheng, Xin Gui, Tianming Li, Hu Pu and Dongdong Lu

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Oncotarget. 2015; 6:27847-27864. https://doi.org/10.18632/oncotarget.4443

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Abstract

Haiyan Li1, Jiahui An1, Mengying Wu1, Qidi Zheng1, Xin Gui1, Tianming Li1, Hu Pu1, Dongdong Lu1

1School 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 Skp2 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.


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