PMID- 35697678
OWN - NLM
STAT- MEDLINE
DCOM- 20220615
LR  - 20230119
IS  - 2041-4889 (Electronic)
VI  - 13
IP  - 6
DP  - 2022 Jun 13
TI  - Histone H3K36me2 demethylase KDM2A promotes bladder cancer progression through 
      epigenetically silencing RARRES3.
PG  - 547
LID - 10.1038/s41419-022-04983-7 [doi]
LID - 547
AB  - Epigenetic dysregulation contributes to bladder cancer tumorigenesis. H3K36me2 
      demethylase KDM2A functions as an important epigenetic regulator of cell fate in 
      many types of tumors. However, its role in bladder cancer remains unknown. Here, 
      we revealed a positive correlation between KDM2A gene copy number gain and 
      upregulation of KDM2A mRNA expression in bladder cancer. Moreover, a 
      super-enhancer (SE) driving KDM2A transcription was found in high-grade bladder 
      cancer, resulting in a significantly higher expression of KDM2A mRNA compared to 
      that in low-grade bladder tumors. KDM2A knockdown (KD) decreased the 
      proliferation, invasion, and spheroid formation of high-grade bladder cancer 
      cells and inhibited tumor growth in mouse xenograft models. Furthermore, we 
      identified RARRES3 as a key KDM2A target gene. KDM2A suppresses RARRES3 
      expression via demethylation of H3K36me2 in the RARRES3 promoter. Intriguingly, 
      RARRES3 KD attenuated the inhibitory effects of KDM2A depletion on the malignant 
      phenotypes of high-grade bladder cancer cells. The combination of the KDM2A 
      inhibitor IOX1 and the RARRES3 agonist all-trans retinoic acid (ATRA) 
      synergistically inhibited the proliferation of high-grade bladder cancer cells, 
      suggesting that the KDM2A/RARRES3 axis may be a promising therapeutic target for 
      the treatment of high-grade bladder cancer.
CI  - (c) 2022. The Author(s).
FAU - Lu, Bing
AU  - Lu B
AD  - Institute of Urology of Shenzhen University, The Third Affiliated Hospital of 
      Shenzhen University, Shenzhen Luohu Hospital Group, Shenzhen, 518000, China.
FAU - Wei, Jiatian
AU  - Wei J
AD  - Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-sen University), 
      Ministry of Education, Guangzhou, 510080, China.
FAU - Zhou, Houhong
AU  - Zhou H
AD  - Institute of Urology of Shenzhen University, The Third Affiliated Hospital of 
      Shenzhen University, Shenzhen Luohu Hospital Group, Shenzhen, 518000, China.
FAU - Chen, Jie
AU  - Chen J
AD  - Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
FAU - Li, Yuqing
AU  - Li Y
AD  - Institute of Urology of Shenzhen University, The Third Affiliated Hospital of 
      Shenzhen University, Shenzhen Luohu Hospital Group, Shenzhen, 518000, China.
FAU - Ye, Liefu
AU  - Ye L
AD  - Department of Urology, Fujian Provincial Hospital, 134 Dong Street, Fuzhou, 
      350001, China.
FAU - Zhao, Wei
AU  - Zhao W
AUID- ORCID: 0000-0002-0774-2571
AD  - Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-sen University), 
      Ministry of Education, Guangzhou, 510080, China. zhaowei23@mail.sysu.edu.cn.
FAU - Wu, Song
AU  - Wu S
AUID- ORCID: 0000-0003-3504-1630
AD  - Institute of Urology of Shenzhen University, The Third Affiliated Hospital of 
      Shenzhen University, Shenzhen Luohu Hospital Group, Shenzhen, 518000, China. 
      wusong@szu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220613
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (F-Box Proteins)
RN  - 0 (Histones)
RN  - 0 (PLAAT4 protein, human)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Retinoic Acid)
RN  - EC 1.14.11.- (Histone Demethylases)
RN  - EC 1.14.11.- (Jumonji Domain-Containing Histone Demethylases)
RN  - EC 1.14.11.27 (KDM2A protein, human)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Proliferation/genetics
MH  - *F-Box Proteins/metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - Histone Demethylases/metabolism
MH  - Histones/metabolism
MH  - Humans
MH  - Jumonji Domain-Containing Histone Demethylases/metabolism
MH  - Mice
MH  - RNA, Messenger/genetics
MH  - Receptors, Retinoic Acid/*genetics
MH  - *Urinary Bladder Neoplasms/genetics
PMC - PMC9192503
COIS- The authors declare no competing interests.
EDAT- 2022/06/14 06:00
MHDA- 2022/06/16 06:00
PMCR- 2022/06/13
CRDT- 2022/06/13 23:14
PHST- 2022/01/28 00:00 [received]
PHST- 2022/05/26 00:00 [accepted]
PHST- 2022/05/22 00:00 [revised]
PHST- 2022/06/13 23:14 [entrez]
PHST- 2022/06/14 06:00 [pubmed]
PHST- 2022/06/16 06:00 [medline]
PHST- 2022/06/13 00:00 [pmc-release]
AID - 10.1038/s41419-022-04983-7 [pii]
AID - 4983 [pii]
AID - 10.1038/s41419-022-04983-7 [doi]
PST - epublish
SO  - Cell Death Dis. 2022 Jun 13;13(6):547. doi: 10.1038/s41419-022-04983-7.