CHML is an NRF2 target gene that regulates mTOR function.
Matthew DodsonWujing DaiAnnadurai AnandhanCody J SchmidlinPengfei LiuNathan C WilsonYongyi WeiNaoya KitamuraJames J GalliganAikseng OoiEli ChapmanDonna D ZhangPublished in: Molecular oncology (2022)
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.
Keyphrases
- oxidative stress
- transcription factor
- case report
- cell proliferation
- genome wide
- induced apoptosis
- small cell lung cancer
- nuclear factor
- gene expression
- papillary thyroid
- genome wide identification
- single cell
- poor prognosis
- squamous cell carcinoma
- binding protein
- copy number
- signaling pathway
- dna damage
- machine learning
- big data
- photodynamic therapy
- small molecule
- cancer therapy
- squamous cell
- protein protein
- inflammatory response
- immune response
- young adults
- endoplasmic reticulum stress
- data analysis
- amino acid
- brain metastases
- cell cycle arrest
- epidermal growth factor receptor
- dna damage response