PMID- 35184380
OWN - NLM
STAT- MEDLINE
DCOM- 20220421
LR  - 20230415
IS  - 1878-0261 (Electronic)
IS  - 1574-7891 (Print)
IS  - 1574-7891 (Linking)
VI  - 16
IP  - 8
DP  - 2022 Apr
TI  - CHML is an NRF2 target gene that regulates mTOR function.
PG  - 1714-1727
LID - 10.1002/1878-0261.13194 [doi]
AB  - The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is 
      often highly expressed in non-small cell lung cancer (NSCLC). Through its target 
      genes, NRF2 enhances cancer progression and chemo/radioresistance, leading to a 
      poorer prognosis in patients with high NRF2 expression. In this study, we 
      identified CHM-like Rab escort protein (CHML; encoding Rep2) as an NRF2 target 
      gene with an antioxidant response element (ARE) in its promoter region (-1622 to 
      -1612). Analysis of patient data curated by The Cancer Genome Atlas (TCGA) and 
      Oncomine databases revealed that CHML mRNA expression was elevated in lung 
      adenocarcinoma (LUAD) patient tumor tissues and correlated with decreased patient 
      survival. Immunohistochemistry (IHC) analysis of normal versus lung cancer 
      patient tissues revealed that Rep2 protein levels were higher in lung tumors 
      compared with normal tissue, which also correlated with increased levels of NRF2. 
      Importantly, siRNA-mediated knockdown of CHML/Rep2 in A549 NSCLC cells decreased 
      their ability to proliferate. Mechanistically, Rep2 mediates mTOR function, as 
      loss of Rep2 inhibited, whereas overexpression enhanced, mTOR translocation and 
      activation at the lysosome. Our findings identify a novel NRF2-Rep2-dependent 
      regulation of mTOR function.
CI  - (c) 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on 
      behalf of Federation of European Biochemical Societies.
FAU - Dodson, Matthew
AU  - Dodson M
AD  - Department of Pharmacology and Toxicology, College of Pharmacy, University of 
      Arizona, Tucson, AZ, USA.
FAU - Dai, Wujing
AU  - Dai W
AD  - Department of Pharmacology and Toxicology, College of Pharmacy, University of 
      Arizona, Tucson, AZ, USA.
FAU - Anandhan, Annadurai
AU  - Anandhan A
AD  - Department of Pharmacology and Toxicology, College of Pharmacy, University of 
      Arizona, Tucson, AZ, USA.
FAU - Schmidlin, Cody J
AU  - Schmidlin CJ
AD  - Department of Pharmacology and Toxicology, College of Pharmacy, University of 
      Arizona, Tucson, AZ, USA.
FAU - Liu, Pengfei
AU  - Liu P
AD  - Department of Pharmacology and Toxicology, College of Pharmacy, University of 
      Arizona, Tucson, AZ, USA.
FAU - Wilson, Nathan C
AU  - Wilson NC
AD  - Department of Pharmacology and Toxicology, College of Pharmacy, University of 
      Arizona, Tucson, AZ, USA.
FAU - Wei, Yongyi
AU  - Wei Y
AD  - Department of Pharmacology and Toxicology, College of Pharmacy, University of 
      Arizona, Tucson, AZ, USA.
FAU - Kitamura, Naoya
AU  - Kitamura N
AD  - Department of Pharmacology and Toxicology, College of Pharmacy, University of 
      Arizona, Tucson, AZ, USA.
FAU - Galligan, James J
AU  - Galligan JJ
AD  - Department of Pharmacology and Toxicology, College of Pharmacy, University of 
      Arizona, Tucson, AZ, USA.
FAU - Ooi, Aikseng
AU  - Ooi A
AD  - Department of Pharmacology and Toxicology, College of Pharmacy, University of 
      Arizona, Tucson, AZ, USA.
FAU - Chapman, Eli
AU  - Chapman E
AD  - Department of Pharmacology and Toxicology, College of Pharmacy, University of 
      Arizona, Tucson, AZ, USA.
FAU - Zhang, Donna D
AU  - Zhang DD
AUID- ORCID: 0000-0002-8972-697X
AD  - Department of Pharmacology and Toxicology, College of Pharmacy, University of 
      Arizona, Tucson, AZ, USA.
AD  - University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
LA  - eng
GR  - R01 CA226920/CA/NCI NIH HHS/United States
GR  - T32 ES007091/ES/NIEHS NIH HHS/United States
GR  - P30 ES006694/ES/NIEHS NIH HHS/United States
GR  - R35 ES031575/ES/NIEHS NIH HHS/United States
GR  - R35 GM137910/GM/NIGMS NIH HHS/United States
GR  - P42 ES004940/ES/NIEHS NIH HHS/United States
GR  - R01 ES031463/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20220228
PL  - United States
TA  - Mol Oncol
JT  - Molecular oncology
JID - 101308230
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (CHML protein, human)
RN  - 0 (Fatty Acids, Unsaturated)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (cytotropic heterogeneous molecular lipid)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - *Carcinoma, Non-Small-Cell Lung/pathology
MH  - Cell Line, Tumor
MH  - Fatty Acids, Unsaturated
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - *Lung Neoplasms/pathology
MH  - NF-E2-Related Factor 2/genetics/metabolism
MH  - TOR Serine-Threonine Kinases/genetics/metabolism
PMC - PMC9019883
OTO - NOTNLM
OT  - CHML/REP2
OT  - NRF2
OT  - NSCLC
OT  - mTOR
COIS- The authors have no conflicts of interest to declare.
EDAT- 2022/02/21 06:00
MHDA- 2022/04/22 06:00
PMCR- 2022/04/01
CRDT- 2022/02/20 20:40
PHST- 2022/01/25 00:00 [revised]
PHST- 2021/08/19 00:00 [received]
PHST- 2022/02/17 00:00 [accepted]
PHST- 2022/02/21 06:00 [pubmed]
PHST- 2022/04/22 06:00 [medline]
PHST- 2022/02/20 20:40 [entrez]
PHST- 2022/04/01 00:00 [pmc-release]
AID - MOL213194 [pii]
AID - 10.1002/1878-0261.13194 [doi]
PST - ppublish
SO  - Mol Oncol. 2022 Apr;16(8):1714-1727. doi: 10.1002/1878-0261.13194. Epub 2022 Feb 
      28.