PMID- 32843065
OWN - NLM
STAT- MEDLINE
DCOM- 20210528
LR  - 20210528
IS  - 1476-4598 (Electronic)
IS  - 1476-4598 (Linking)
VI  - 19
IP  - 1
DP  - 2020 Aug 25
TI  - Upregulation of METTL14 mediates the elevation of PERP mRNA N(6) adenosine 
      methylation promoting the growth and metastasis of pancreatic cancer.
PG  - 130
LID - 10.1186/s12943-020-01249-8 [doi]
LID - 130
AB  - BACKGROUND: Pancreatic cancer is one of the most lethal human cancers. 
      N(6)-methyladenosine (m(6)A), a common eukaryotic mRNA modification, plays 
      critical roles in both physiological and pathological processes. However, its 
      role in pancreatic cancer remains elusive. METHODS: LC/MS was used to profile 
      m(6)A levels in pancreatic cancer and normal tissues. Bioinformatics analysis, 
      real-time PCR, immunohistochemistry, and western blotting were used to identify 
      the role of m(6)A regulators in pancreatic cancer. The biological effects of 
      methyltransferase-like 14 (METTL14), an mRNA methylase, were investigated using 
      in vitro and in vivo models. MeRIP-Seq and RNA-Seq were used to assess the 
      downstream targets of METTL14. RESULTS: We found that the m(6)A levels were 
      elevated in approximately 70% of the pancreatic cancer samples. Furthermore, we 
      demonstrated that METTL14 is the major enzyme that modulates m(6)A methylation 
      (frequency and site of methylation). METTL14 overexpression markedly promoted 
      pancreatic cancer cell proliferation and migration both in vitro and in vivo, via 
      direct targeting of the downstream PERP mRNA (p53 effector related to PMP-22) in 
      an m(6)A-dependent manner. Methylation of the target adenosine lead to increased 
      PERP mRNA turnover, thus decreasing PERP (mRNA and protein) levels in pancreatic 
      cancer cells. CONCLUSIONS: Our data suggest that the upregulation of METTL14 
      leads to the decrease of PERP levels via m(6)A modification, promoting the growth 
      and metastasis of pancreatic cancer; therefore METTL14 is a potential therapeutic 
      target for its treatment.
FAU - Wang, Min
AU  - Wang M
AD  - Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, 
      Wuhan, 430030, Hubei, China.
FAU - Liu, Jun
AU  - Liu J
AD  - Department of Chemistry, Department of Biochemistry and Molecular Biology, 
      Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The 
      University of Chicago, Chicago, IL, 60637, USA.
FAU - Zhao, Yan
AU  - Zhao Y
AD  - Department of Trauma Surgery, Affiliated Tongji Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan, 430030, China.
FAU - He, Ruizhi
AU  - He R
AD  - Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, 
      Wuhan, 430030, Hubei, China.
FAU - Xu, Xiaodong
AU  - Xu X
AD  - Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou 
      University, Zhengzhou, 450000, China.
FAU - Guo, Xingjun
AU  - Guo X
AD  - Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, 
      Wuhan, 430030, Hubei, China.
FAU - Li, Xu
AU  - Li X
AD  - Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, 
      Wuhan, 430030, Hubei, China.
FAU - Xu, Simiao
AU  - Xu S
AD  - Department of Endocrinology, Affiliated Tongji Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan, 430030, China.
FAU - Miao, Ji
AU  - Miao J
AD  - Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, 
      Boston, MA, 02115, USA.
FAU - Guo, Jianpin
AU  - Guo J
AD  - The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
AD  - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, 330 Brookline Avenue, Boston, MA, 02215, USA.
FAU - Zhang, Hang
AU  - Zhang H
AD  - Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, 
      Wuhan, 430030, Hubei, China.
FAU - Gong, Jun
AU  - Gong J
AD  - Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, 
      Wuhan, 430030, Hubei, China.
FAU - Zhu, Feng
AU  - Zhu F
AD  - Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, 
      Wuhan, 430030, Hubei, China.
FAU - Tian, Rui
AU  - Tian R
AD  - Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, 
      Wuhan, 430030, Hubei, China.
FAU - Shi, Chengjian
AU  - Shi C
AD  - Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, 
      Wuhan, 430030, Hubei, China.
FAU - Peng, Feng
AU  - Peng F
AD  - Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, 
      Wuhan, 430030, Hubei, China.
FAU - Feng, Yechen
AU  - Feng Y
AD  - Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, 
      Wuhan, 430030, Hubei, China.
FAU - Yu, Shuo
AU  - Yu S
AD  - Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, 
      Wuhan, 430030, Hubei, China.
FAU - Xie, Yu
AU  - Xie Y
AD  - Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, 
      Wuhan, 430030, Hubei, China.
FAU - Jiang, Jianxin
AU  - Jiang J
AD  - Department of Hepatic-Biliary-Pancreatic Surgery, Renmin Hospital of Wuhan 
      University, Wuhan, 430060, China.
FAU - Li, Min
AU  - Li M
AD  - Department of Medicine, The University of Oklahoma Health Sciences Center, 
      Oklahoma City, OK, USA. Min-Li@ouhsc.edu.
FAU - Wei, Wenyi
AU  - Wei W
AD  - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, 330 Brookline Avenue, Boston, MA, 02215, USA. wwei2@bidmc.harvard.edu.
FAU - He, Chuan
AU  - He C
AD  - Department of Chemistry, Department of Biochemistry and Molecular Biology, 
      Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The 
      University of Chicago, Chicago, IL, 60637, USA. chuanhe@uchicago.edu.
FAU - Qin, Renyi
AU  - Qin R
AD  - Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, 
      Wuhan, 430030, Hubei, China. ryqin@tjh.tjmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200825
PL  - England
TA  - Mol Cancer
JT  - Molecular cancer
JID - 101147698
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Membrane Proteins)
RN  - 0 (PERP protein, human)
RN  - 0 (RNA, Messenger)
RN  - 17124-24-2 (N(6)-methoxyadenine)
RN  - EC 2.1.1.- (METTL14 protein, human)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - JAC85A2161 (Adenine)
SB  - IM
MH  - Adenine/*analogs & derivatives/metabolism
MH  - Animals
MH  - Binding Sites
MH  - Biomarkers, Tumor
MH  - Cell Line, Tumor
MH  - Disease Models, Animal
MH  - *Gene Expression Regulation, Neoplastic
MH  - Gene Silencing
MH  - Genes, Tumor Suppressor
MH  - Heterografts
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Membrane Proteins/*genetics
MH  - Methylation
MH  - Methyltransferases/*genetics/metabolism
MH  - Mice
MH  - Neoplasm Metastasis
MH  - Neoplasm Staging
MH  - Pancreatic Neoplasms/*genetics/*metabolism/mortality/pathology
MH  - Prognosis
MH  - Protein Binding
MH  - RNA Stability
MH  - RNA, Messenger/*genetics/metabolism
PMC - PMC7446161
OTO - NOTNLM
OT  - METTL14
OT  - N6-methyladenosine
OT  - PERP
OT  - Pancreatic cancer
OT  - m6A
COIS- C.H. is the scientific founder of Accent Therapeutics and a member of its 
      scientific advisory board. All other authors declare no competing financial 
      interests.
EDAT- 2020/08/28 06:00
MHDA- 2021/05/29 06:00
PMCR- 2020/08/25
CRDT- 2020/08/27 06:00
PHST- 2020/02/29 00:00 [received]
PHST- 2020/08/13 00:00 [accepted]
PHST- 2020/08/27 06:00 [entrez]
PHST- 2020/08/28 06:00 [pubmed]
PHST- 2021/05/29 06:00 [medline]
PHST- 2020/08/25 00:00 [pmc-release]
AID - 10.1186/s12943-020-01249-8 [pii]
AID - 1249 [pii]
AID - 10.1186/s12943-020-01249-8 [doi]
PST - epublish
SO  - Mol Cancer. 2020 Aug 25;19(1):130. doi: 10.1186/s12943-020-01249-8.