PMID- 34322883
OWN - NLM
STAT- MEDLINE
DCOM- 20220119
LR  - 20231213
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 74
IP  - 6
DP  - 2021 Dec
TI  - LSD1-Demethylated LINC01134 Confers Oxaliplatin Resistance Through SP1-Induced 
      p62 Transcription in HCC.
PG  - 3213-3234
LID - 10.1002/hep.32079 [doi]
AB  - 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.
CI  - (c) 2021 by the American Association for the Study of Liver Diseases.
FAU - Ma, Luyuan
AU  - Ma L
AUID- ORCID: 0000-0002-1816-5175
AD  - Department of Infectious Diseases, the Third Hospital of Hebei Medical 
      University, Shijiazhuang, China.
AD  - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 
      China.
FAU - Xu, An
AU  - Xu A
AD  - Department of Oncology, Second Medical Center of Chinese PLA General Hospital, 
      Beijing, China.
FAU - Kang, Lei
AU  - Kang L
AD  - Department of Nuclear Medicine, Peking University First Hospital, Beijing, China.
FAU - Cong, Rui
AU  - Cong R
AD  - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 
      China.
FAU - Fan, Zhongyi
AU  - Fan Z
AD  - Department of Oncology and Hematology, Shenzhen Third People's Hospital, Second 
      Hospital Affiliated to Southern University of Science and Technology, Shenzhen, 
      China.
FAU - Zhu, Xiang
AU  - Zhu X
AD  - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 
      China.
FAU - Huo, Nan
AU  - Huo N
AD  - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 
      China.
FAU - Liu, Wenpeng
AU  - Liu W
AD  - Department of Infectious Diseases, the Third Hospital of Hebei Medical 
      University, Shijiazhuang, China.
FAU - Xue, Chunyuan
AU  - Xue C
AD  - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 
      China.
FAU - Ji, Quanbo
AU  - Ji Q
AD  - Department of Orthopedics, First Medical Center of Chinese PLA General Hospital, 
      Beijing, China.
FAU - Li, Wenchao
AU  - Li W
AD  - Seventh Medical Center of Chinese PLA General Hospital, Beijing, China.
FAU - Chu, Zhong
AU  - Chu Z
AD  - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 
      China.
FAU - Kang, Xiaofeng
AU  - Kang X
AD  - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 
      China.
FAU - Wang, Yadong
AU  - Wang Y
AD  - Department of Infectious Diseases, the Third Hospital of Hebei Medical 
      University, Shijiazhuang, China.
FAU - Sun, Zhijia
AU  - Sun Z
AD  - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 
      China.
FAU - Han, Yuchen
AU  - Han Y
AD  - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 
      China.
FAU - Liu, Hanxiao
AU  - Liu H
AD  - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 
      China.
FAU - Gao, Xiang
AU  - Gao X
AD  - State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute 
      of Pharmacology and Toxicology, Beijing, China.
FAU - Han, Juqiang
AU  - Han J
AD  - Seventh Medical Center of Chinese PLA General Hospital, Beijing, China.
FAU - You, Hua
AU  - You H
AD  - Department of Oncology, Affiliated Cancer Hospital & Institute of Guangzhou 
      Medical University, Guangzhou, China.
FAU - Zhao, Caiyan
AU  - Zhao C
AD  - Department of Infectious Diseases, the Third Hospital of Hebei Medical 
      University, Shijiazhuang, China.
FAU - Xu, Xiaojie
AU  - Xu X
AD  - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 
      China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211005
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Antineoplastic Agents)
RN  - 0 (P62 protein, human)
RN  - 0 (RNA, Long Noncoding)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Sp1 Transcription Factor)
RN  - 0 (SP1 protein, human)
RN  - 04ZR38536J (Oxaliplatin)
RN  - EC 1.14.11.- (Histone Demethylases)
RN  - EC 1.5.- (KDM1A protein, human)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*therapeutic use
MH  - Apoptosis
MH  - Carcinoma, Hepatocellular/*drug therapy/metabolism
MH  - Cell Line, Tumor
MH  - Demethylation
MH  - Drug Resistance, Neoplasm/genetics
MH  - Hep G2 Cells
MH  - Histone Demethylases/*metabolism
MH  - Humans
MH  - Immunoprecipitation
MH  - In Situ Hybridization, Fluorescence
MH  - Liver Neoplasms/*drug therapy/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Nude
MH  - Neoplasm Transplantation
MH  - Oxaliplatin/*therapeutic use
MH  - Oxidative Stress
MH  - RNA, Long Noncoding/genetics/*metabolism
MH  - RNA-Binding Proteins/*metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Sp1 Transcription Factor/*metabolism
EDAT- 2021/07/30 06:00
MHDA- 2022/01/20 06:00
CRDT- 2021/07/29 07:04
PHST- 2021/07/05 00:00 [revised]
PHST- 2020/11/06 00:00 [received]
PHST- 2021/07/08 00:00 [accepted]
PHST- 2021/07/30 06:00 [pubmed]
PHST- 2022/01/20 06:00 [medline]
PHST- 2021/07/29 07:04 [entrez]
AID - 10.1002/hep.32079 [doi]
PST - ppublish
SO  - Hepatology. 2021 Dec;74(6):3213-3234. doi: 10.1002/hep.32079. Epub 2021 Oct 5.