PMID- 33783988
OWN - NLM
STAT- MEDLINE
DCOM- 20220110
LR  - 20240331
IS  - 2001-1326 (Electronic)
IS  - 2001-1326 (Linking)
VI  - 11
IP  - 3
DP  - 2021 Mar
TI  - AMD1 upregulates hepatocellular carcinoma cells stemness by FTO mediated mRNA 
      demethylation.
PG  - e352
LID - 10.1002/ctm2.352 [doi]
LID - e352
AB  - BACKGROUND: S-adenosylmethionine decarboxylase proenzyme (AMD1) is a key enzyme 
      involved in the synthesis of spermine (SPM) and spermidine (SPD), which are 
      associated with multifarious cellular processes. It is also found to be an 
      oncogene in multiple cancers and a potential target for tumor therapy. 
      Nevertheless, the role AMD1 plays in hepatocellular carcinoma (HCC) is still 
      unknown. METHODS: HCC samples were applied to detect AMD1 expression and evaluate 
      its associations with clinicopathological features and prognosis. Subcutaneous 
      and orthotopic tumor mouse models were constructed to analyze the proliferation 
      and metastasis of HCC cells after AMD1 knockdown or overexpression. Drug 
      sensitive and tumor sphere assay were performed to investigate the effect of AMD1 
      on HCC cells stemness. Real-time quantitative PCR (qRT-PCR), western blot, 
      immunohistochemical (IHC) and m6A-RNA immunoprecipitation (Me-RIP) 
      sequencing/qPCR were applied to explore the potential mechanisms of AMD1 in HCC. 
      Furthermore, immunofluorescence, co-IP (Co-IP) assays, and mass spectrometric 
      (MS) analyses were performed to verify the proteins interacting with AMD1. 
      RESULTS: AMD1 was enriched in human HCC tissues and suggested a poor prognosis. 
      High AMD1 level could promote SRY-box transcription factor 2 (SOX2), Kruppel like 
      factor 4 (KLF4), and NANOG expression of HCC cells through obesity-associated 
      protein (FTO)-mediated mRNA demethylation. Mechanistically, high AMD1 expression 
      increased the levels of SPD in HCC cells, which could modify the scaffold 
      protein, Ras GTPase-activating-like protein 1 (IQGAP1) and enhance the 
      interaction between IQGAP1 and FTO. This interaction could enhance the 
      phosphorylation and decrease the ubiquitination of FTO. CONCLUSIONS: AMD1 could 
      stabilize the interaction of IQGAP1 with FTO, which then promotes FTO expression 
      and increases HCC stemness. AMD1 shows prospects as a prognostic predictor and a 
      therapeutic target for HCC.
CI  - (c) 2021 The Authors. Clinical and Translational Medicine published by John Wiley & 
      Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
FAU - Bian, Xinyu
AU  - Bian X
AD  - Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of 
      Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
AD  - Department of Radiation Oncology, Affiliated Hospital of Nanjing University of 
      Chinese Medicine, Nanjing, Jiangsu, China.
FAU - Shi, Dongmin
AU  - Shi D
AD  - Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of 
      Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
FAU - Xing, Kailin
AU  - Xing K
AD  - Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of 
      Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
FAU - Zhou, Hongxin
AU  - Zhou H
AD  - Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of 
      Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
FAU - Lu, Lili
AU  - Lu L
AD  - Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of 
      Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
FAU - Yu, Dahai
AU  - Yu D
AD  - Department of Radiation Oncology, Affiliated Hospital of Nanjing University of 
      Chinese Medicine, Nanjing, Jiangsu, China.
FAU - Wu, Weizhong
AU  - Wu W
AUID- ORCID: 0000-0002-4936-7220
AD  - Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of 
      Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Transl Med
JT  - Clinical and translational medicine
JID - 101597971
RN  - 0 (RNA, Messenger)
RN  - EC 1.14.11.- (FTO protein, mouse)
RN  - EC 1.14.11.33 (Alpha-Ketoglutarate-Dependent Dioxygenase FTO)
RN  - EC 4.1.1.50 (Adenosylmethionine Decarboxylase)
RN  - EC 4.1.1.50 (Amd1 protein, mouse)
SB  - IM
MH  - Adenosylmethionine Decarboxylase/*genetics/metabolism
MH  - Alpha-Ketoglutarate-Dependent Dioxygenase FTO/*genetics/metabolism
MH  - Animals
MH  - Carcinoma, Hepatocellular/*genetics/metabolism
MH  - Cell Proliferation/genetics
MH  - *Demethylation
MH  - Disease Models, Animal
MH  - Humans
MH  - Liver Neoplasms/*genetics/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - RNA, Messenger/genetics/*metabolism
MH  - Stem Cells/metabolism
MH  - Up-Regulation/genetics
PMC - PMC7989706
OTO - NOTNLM
OT  - AMD1
OT  - FTO
OT  - IQGAP1
OT  - N6-methyladenosine
OT  - hepatocellular carcinoma
OT  - polyamination
OT  - stemness
COIS- The authors declare that there is no conflict of interest that could be perceived 
      as prejudicing the impartiality of the research reported.
EDAT- 2021/03/31 06:00
MHDA- 2022/01/11 06:00
PMCR- 2021/03/24
CRDT- 2021/03/30 12:50
PHST- 2021/02/20 00:00 [revised]
PHST- 2020/07/30 00:00 [received]
PHST- 2021/02/23 00:00 [accepted]
PHST- 2021/03/30 12:50 [entrez]
PHST- 2021/03/31 06:00 [pubmed]
PHST- 2022/01/11 06:00 [medline]
PHST- 2021/03/24 00:00 [pmc-release]
AID - CTM2352 [pii]
AID - 10.1002/ctm2.352 [doi]
PST - ppublish
SO  - Clin Transl Med. 2021 Mar;11(3):e352. doi: 10.1002/ctm2.352.