CHML is an NRF2 target gene that regulates mTOR function

Matthew Dodson, Wujing Dai, Annadurai Anandhan, Cody J. Schmidlin, Pengfei Liu, Nathan C. Wilson, Yongyi Wei, Naoya Kitamura, James J. Galligan, Aikseng Ooi, Eli Chapman, Donna D. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1714-1727
Number of pages14
JournalMolecular Oncology
Volume16
Issue number8
DOIs
StatePublished - Apr 2022

Keywords

  • CHML/REP2
  • NRF2
  • NSCLC
  • mTOR

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

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