LSD1-Demethylated LINC01134 Confers Oxaliplatin Resistance Through SP1-Induced p62 Transcription in HCC

Ma, Luyuan1,2; Xu, An3; Kang, Lei4; Cong, Rui2; Fan, Zhongyi5; Zhu, Xiang2; Huo, Nan2; Liu, Wenpeng1; Xue, Chunyuan2; Ji, Quanbo6; Li, Wenchao7; Chu, Zhong2; Kang, Xiaofeng2; Wang, Yadong1; Sun, Zhijia2; Han, Yuchen2; Liu, Hanxiao2; Gao, Xiang8; Han, Juqiang7; You, Hua9; Zhao, Caiyan1; Xu, Xiaojie2

2021-10-01

10.1002/hep.32079

HEPATOLOGY   影响因子和分区

0270-9139

1527-3350

Background and Aims Oxaliplatin (OXA) is one of the most common chemotherapeutics in advanced hepatocellular carcinoma (HCC), the resistance of which poses a big challenge. Long noncoding RNAs (lncRNAs) play vital roles in chemoresistance. Therefore, elucidating the underlying mechanisms and identifying predictive lncRNAs for OXA resistance is needed urgently. Methods RNA sequencing (RNA-seq) and fluorescence in situ hybridization (FISH) were used to investigate the OXA-resistant (OXA-R) lncRNAs. Survival analysis was performed to determine the clinical significance of homo sapiens long intergenic non-protein-coding RNA 1134 (LINC01134) and p62 expression. Luciferase, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and chromatin isolation by RNA purification (ChIRP) assays were used to explore the mechanisms by which LINC01134 regulates p62 expression. The effects of LINC01134/SP1/p62 axis on OXA resistance were evaluated using cell viability, apoptosis, and mitochondrial function and morphology analysis. Xenografts were used to estimate the in vivo regulation of OXA resistance by LINC01134/SP1/p62 axis. ChIP, cell viability, and xenograft assays were used to identify the demethylase for LINC01134 up-regulation in OXA resistance. Results LINC01134 was identified as one of the most up-regulated lncRNAs in OXA-R cells. Higher LINC01134 expression predicted poorer OXA therapeutic efficacy. LINC01134 activates anti-oxidative pathway through p62 by recruiting transcription factor SP1 to the p62 promoter. The LINC01134/SP1/p62 axis regulates OXA resistance by altering cell viability, apoptosis, and mitochondrial homeostasis both in vitro and in vivo. Furthermore, the demethylase, lysine specific demethylase 1 (LSD1) was responsible for LINC01134 up-regulation in OXA-R cells. In patients with HCC, LINC01134 expression was positively correlated with p62 and LSD1 expressions, whereas SP1 expression positively correlated with p62 expression. Conclusions LSD1/LINC01134/SP1/p62 axis is critical for OXA resistance in HCC. Evaluating LINC01134 expression in HCC will be effective in predicting OXA efficacy. In treatment-naive patients, targeting the LINC01134/SP1/p62 axis may be a promising strategy to overcome OXA chemoresistance.

SCI

英语

其他

National Natural Science Foundation of China[81822037,81972446,81871385,81902250,81902440,81972734,81702936,81970512,81903088,81911530169] ; Innovation Ability Promotion Project of Hebei Infectious Disease Clinical Medical Research Center (S&T Program of Hebei)[20577704D] ; Beijing Science Foundation for Distinguished Young Scholars[JQ19028] ; Beijing Science Foundation[7192196] ; Key Basic Research project of Basic Strengthening Program[2020-JCJQ-ZD-253-04] ; PKU Medicine-X Youth Program[PKU2021LCXQ023] ; Open Funding Project of the State Key Laboratory of Biochemical Engineering[2020KF-01]

Gastroenterology & Hepatology

Gastroenterology & Hepatology

WOS:000704457000001

WILEY

CLINICAL MEDICINE

Web of Science

1.Hebei Med Univ, Dept Infect Dis, Hosp 3, 168 Xiangjiang Rd, Shijiazhuang 050000, Hebei, Peoples R China
2.Beijing Inst Biotechnol, Dept Genet Engn, Beijing, Peoples R China
3.Chinese Peoples Liberat Army Gen Hosp, Med Ctr 2, Dept Oncol, Beijing, Peoples R China
4.Peking Univ First Hosp, Dept Nucl Med, Beijing, Peoples R China
5.Southern Univ Sci & Technol, Hosp 2, Shenzhen Peoples Hosp 3, Dept Oncol & Hematol, Shenzhen, Peoples R China
6.Chinese Peoples Liberat Army Gen Hosp, Dept Orthoped, Med Ctr 1, Beijing, Peoples R China
7.Chinese Peoples Liberat Army Gen Hosp, Med Ctr 7, Beijing, Peoples R China
8.Beijing Inst Pharmacol & Toxicol, State Key Lab Toxicol & Med Countermeasures, 27 Taiping Rd, Beijing 100850, Peoples R China
9.Guangzhou Med Univ, Affiliated Canc Hosp & Inst, Dept Oncol, 78 Heng Jigang Rd, Guangzhou 510095, Peoples R China

Ma, Luyuan,Xu, An,Kang, Lei,et al. LSD1-Demethylated LINC01134 Confers Oxaliplatin Resistance Through SP1-Induced p62 Transcription in HCC[J]. HEPATOLOGY,2021.

Ma, Luyuan.,Xu, An.,Kang, Lei.,Cong, Rui.,Fan, Zhongyi.,...&Xu, Xiaojie.(2021).LSD1-Demethylated LINC01134 Confers Oxaliplatin Resistance Through SP1-Induced p62 Transcription in HCC.HEPATOLOGY.

Ma, Luyuan,et al."LSD1-Demethylated LINC01134 Confers Oxaliplatin Resistance Through SP1-Induced p62 Transcription in HCC".HEPATOLOGY (2021).