PMID- 38467635
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240315
IS  - 2058-7716 (Print)
IS  - 2058-7716 (Electronic)
IS  - 2058-7716 (Linking)
VI  - 10
IP  - 1
DP  - 2024 Mar 11
TI  - mTORC1 accelerates osteosarcoma progression via m(6)A-dependent stabilization of 
      USP7 mRNA.
PG  - 127
LID - 10.1038/s41420-024-01893-9 [doi]
LID - 127
AB  - Osteosarcoma (OS) is considered a sex steroid hormone-dependent bone tumor. The 
      development and progression of OS are regulated by 17beta-estradiol (E2). However, 
      the detailed mechanisms of E2-modulated OS progression remained to be elucidated. 
      Here, we found that E2-activated mammalian target of rapamycin (mTOR) signaling 
      promoted N6-methyladenosine (m(6)A) modification through regulating WTAP. 
      Inhibition of mTOR complex 1 (mTORC1) reversed E2-activated WTAP expression. 
      Meanwhile, inhibition of mTORC1 suppressed OS cell proliferation and migration. 
      Deficiency of TSC2 activated mTORC1 signaling and enhanced OS cell proliferation 
      and migration, while abrogated by Rapamycin. Interestingly, mTOMC1 promoted mRNA 
      stability of ubiquitin-specific protease 7 (USP7) through m(6)A modification. 
      Loss of USP7 suppressed the proliferation, migration, and ASC specks, while 
      promoted apoptosis of OS cells. USP7 interacted with NLRP3 and deubiquitinated 
      NLRP3 through K48-ubiquitination. USP7 was upregulated and positive correlation 
      with NLRP3 in OS patients with high level of E2. Loss of USP7 suppressed the 
      progression of OS via inhibiting NLRP3 inflammasome signaling pathway. Our 
      results demonstrated that E2-activtated mTORC1 promoted USP7 stability, which 
      promoted OS cell proliferation and migration via upregulating NLRP3 expression 
      and enhancing NLRP3 inflammasome signaling pathway. These results discover a 
      novel mechanism of E2 regulating OS progression and provide a promising 
      therapeutic target for OS progression.
CI  - (c) 2024. The Author(s).
FAU - Yang, Zhengming
AU  - Yang Z
AUID- ORCID: 0009-0009-5474-6856
AD  - Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang 
      University, Hangzhou, China. 2200013@zju.edu.cn.
AD  - Orthopedics Research Institute of Zhejiang University, Hangzhou, China. 
      2200013@zju.edu.cn.
FAU - Yu, Wei
AU  - Yu W
AD  - Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang 
      University, Hangzhou, China.
AD  - Orthopedics Research Institute of Zhejiang University, Hangzhou, China.
FAU - Xu, Ankai
AU  - Xu A
AD  - Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang 
      University, Hangzhou, China.
AD  - Orthopedics Research Institute of Zhejiang University, Hangzhou, China.
FAU - Liu, Bing
AU  - Liu B
AD  - Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang 
      University, Hangzhou, China.
AD  - Orthopedics Research Institute of Zhejiang University, Hangzhou, China.
FAU - Jin, Libin
AU  - Jin L
AD  - Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang 
      University, Hangzhou, China.
AD  - Orthopedics Research Institute of Zhejiang University, Hangzhou, China.
FAU - Tao, Huimin
AU  - Tao H
AD  - Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang 
      University, Hangzhou, China.
AD  - Orthopedics Research Institute of Zhejiang University, Hangzhou, China.
FAU - Wang, Dimin
AU  - Wang D
AD  - Department of Reproductive endocrinology, School of Medicine, Zhejiang 
      University, Hangzhou, China. diminwang@zju.edu.cn.
LA  - eng
GR  - LY20H160025/Natural Science Foundation of Zhejiang Province (Zhejiang Provincial 
      Natural Science Foundation)/
PT  - Journal Article
DEP - 20240311
PL  - United States
TA  - Cell Death Discov
JT  - Cell death discovery
JID - 101665035
PMC - PMC10928159
COIS- The authors declare no competing interests.
EDAT- 2024/03/12 06:43
MHDA- 2024/03/12 06:44
PMCR- 2024/03/11
CRDT- 2024/03/12 00:16
PHST- 2023/12/19 00:00 [received]
PHST- 2024/02/27 00:00 [accepted]
PHST- 2024/02/21 00:00 [revised]
PHST- 2024/03/12 06:44 [medline]
PHST- 2024/03/12 06:43 [pubmed]
PHST- 2024/03/12 00:16 [entrez]
PHST- 2024/03/11 00:00 [pmc-release]
AID - 10.1038/s41420-024-01893-9 [pii]
AID - 1893 [pii]
AID - 10.1038/s41420-024-01893-9 [doi]
PST - epublish
SO  - Cell Death Discov. 2024 Mar 11;10(1):127. doi: 10.1038/s41420-024-01893-9.