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Role of NADPH oxidase NOX4 in regulating redox and metabolic homeostasis in liver cancer

IRB Barcelona BioMed Seminars
8 Oct 21

Speaker: Isabel Fabregat, PhD - GL TGF-β and Cancer Group. Oncobell Program. Bellvitge Biomedical Research Institute (IDIBELL),  University of Barcelona and CIBEREHD-ISCIII, L’Hospitalet, Barcelona, Spain.

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Presentation


Organizer: IRB Barcelona

Date: Friday  08 October 2021, 12.00h

Title: Role of NADPH oxidase NOX4 in regulating redox and metabolic homeostasis

Host: Manuel Serrano, PhD - GL  Cellular Plasticity and  Disease

Place: Auditorium - PCB (Barcelona Science Park)

 

ABSTRACT:

TGF-β and Cancer Group. Oncobell Program. Bellvitge Biomedical Research Institute (IDIBELL),  University of Barcelona and CIBEREHD-ISCIII, L’Hospitalet, Barcelona, Spain.

The NADPH oxidase NOX4 plays a tumor suppressor function in hepatocellular carcinoma (HCC). Silencing NOX4 confers higher cell proliferative and migratory capacity and increased tumorigenic potential. NOX4 gene deletions are frequent in HCC, correlating with higher tumour grade. To determine the molecular mechanisms regulated by NOX4, we performed in vitro experiments of loss- or gain-of-function, as well as in vivo experimental hepatocarcinogenesis in NOX4-/- mice and analyses in human HCC samples. Results pointed to the identification of MYC as negatively regulated by NOX4, which mediates mitochondria dynamics and a transcriptional program leading to increased oxidative metabolism, enhanced use of both glucose and fatty acids and, overall, higher energetic capacity and ATP levels. NOX4 deletion induces a redox imbalance that produces activation of the NRF2 pathway, which is upstream from the increase in MYC expression. In conclusion, loss of NOX4 induces metabolic reprogramming in a NRF2/Myc-dependent manner to promote HCC progression.