PMID- 34372882
OWN - NLM
STAT- MEDLINE
DCOM- 20210819
LR  - 20220531
IS  - 1479-5876 (Electronic)
IS  - 1479-5876 (Linking)
VI  - 19
IP  - 1
DP  - 2021 Aug 9
TI  - ELK4 promotes the development of gastric cancer by inducing M2 polarization of 
      macrophages through regulation of the KDM5A-PJA2-KSR1 axis.
PG  - 342
LID - 10.1186/s12967-021-02915-1 [doi]
LID - 342
AB  - BACKGROUND: We tried to elaborate the molecular mechanism of ETS-like 
      transcription factor 4 (ELK4) affecting gastric cancer (GC) progression through 
      M2 polarization of macrophages mediated by lysine-specific demethylase 5A 
      (KDM5A)-Praja2 (PJA2)-kinase suppressor of ras 1 (KSR1) axis. METHODS: GC 
      expression dataset was obtained from GEO database, and the downstream regulatory 
      mechanism of ELK4 was predicted. Tumor-associated macrophages (TAMs) were 
      isolated from GC tissues. The interaction among ELK4, KDM5A, PJA2 and KSR1 was 
      analyzed by dual luciferase reporter gene, ChIP and Co-IP assays. The stability 
      of KSR1 protein was detected by cycloheximide (CHX) treatment. After TAMs were 
      co-cultured with HGC-27 cells, HGC-27 cell biological processes were assessed 
      through gain- and loss-of function assays. Tumorigenicity was detected by 
      tumorigenicity test in nude mice. RESULTS: In GC and TAMs, ELK4, KDM5A and KSR1 
      were highly expressed, while PJA2 was lowly expressed. M2 polarization of 
      macrophages promoted the development of GC. ELK4 activated KDM5A by transcription 
      and promoted macrophage M2 polarization. KDM5A inhibited the expression of PJA2 
      by removing H3K4me3 of PJA2 promoter, which promoted M2 polarization of 
      macrophages. PJA2 reduced KSR1 by ubiquitination. ELK4 promoted the 
      proliferative, migrative and invasive potentials of GC cells as well as the 
      growth of GC xenografts by regulating KSR1. CONCLUSION: ELK4 may reduce the 
      PJA2-dependent inhibition of KSR1 by transcriptional activation of KDM5A to 
      promote M2 polarization of macrophages, thus promoting the development of GC.
CI  - (c) 2021. The Author(s).
FAU - Zheng, Lei
AU  - Zheng L
AD  - Department of Oncology, The First Hospital of Qinhuangdao, No. 258, Wenhua Road, 
      Qinhuangdao, 066000, Hebei Province, People's Republic of China.
FAU - Xu, Hongmei
AU  - Xu H
AD  - Department of Oncology, The First Hospital of Qinhuangdao, No. 258, Wenhua Road, 
      Qinhuangdao, 066000, Hebei Province, People's Republic of China.
FAU - Di, Ya
AU  - Di Y
AD  - Department of Oncology, The First Hospital of Qinhuangdao, No. 258, Wenhua Road, 
      Qinhuangdao, 066000, Hebei Province, People's Republic of China.
FAU - Chen, Lanlan
AU  - Chen L
AD  - Department of Oncology, The First Hospital of Qinhuangdao, No. 258, Wenhua Road, 
      Qinhuangdao, 066000, Hebei Province, People's Republic of China.
FAU - Liu, Jiao
AU  - Liu J
AD  - Department of Oncology, The First Hospital of Qinhuangdao, No. 258, Wenhua Road, 
      Qinhuangdao, 066000, Hebei Province, People's Republic of China.
FAU - Kang, Liying
AU  - Kang L
AD  - Department of Oncology, Tianjin Wuqing District People's Hospital, Tianjin, 
      301700, People's Republic of China.
FAU - Gao, Liming
AU  - Gao L
AD  - Department of Oncology, The First Hospital of Qinhuangdao, No. 258, Wenhua Road, 
      Qinhuangdao, 066000, Hebei Province, People's Republic of China. 
      Tshgaoliming@126.com.
LA  - eng
PT  - Journal Article
DEP - 20210809
PL  - England
TA  - J Transl Med
JT  - Journal of translational medicine
JID - 101190741
RN  - 0 (ELK4 protein, human)
RN  - 146481-62-1 (ets-Domain Protein Elk-4)
RN  - EC 1.14.11.- (KDM5A protein, human)
RN  - EC 1.14.11.27 (Retinoblastoma-Binding Protein 2)
RN  - EC 2.3.2.27 (PJA2 protein, human)
RN  - EC 2.3.2.27 (PJA2 protein, mouse)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Humans
MH  - Macrophage Activation
MH  - Macrophages
MH  - Mice
MH  - Mice, Nude
MH  - Retinoblastoma-Binding Protein 2
MH  - *Stomach Neoplasms/genetics
MH  - Transcriptional Activation
MH  - Ubiquitin-Protein Ligases
MH  - ets-Domain Protein Elk-4
PMC - PMC8353876
OTO - NOTNLM
OT  - ELK4
OT  - Gastric cancer
OT  - KDM5A
OT  - KSR1
OT  - Macrophages
OT  - Methylation
OT  - PJA2
OT  - Transcription
OT  - Ubiquitination
COIS- The authors declare that they have no competing interests.
EDAT- 2021/08/11 06:00
MHDA- 2021/08/20 06:00
PMCR- 2021/08/09
CRDT- 2021/08/10 05:36
PHST- 2021/01/02 00:00 [received]
PHST- 2021/05/27 00:00 [accepted]
PHST- 2021/08/10 05:36 [entrez]
PHST- 2021/08/11 06:00 [pubmed]
PHST- 2021/08/20 06:00 [medline]
PHST- 2021/08/09 00:00 [pmc-release]
AID - 10.1186/s12967-021-02915-1 [pii]
AID - 2915 [pii]
AID - 10.1186/s12967-021-02915-1 [doi]
PST - epublish
SO  - J Transl Med. 2021 Aug 9;19(1):342. doi: 10.1186/s12967-021-02915-1.