MYB sustains hypoxic survival of pancreatic cancer cells by facilitating metabolic reprogramming.

Autor:	Anand S; Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA.; Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA., Khan MA; Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA.; Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA., Zubair H; Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA.; Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA., Sudan SK; Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA.; Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA., Vikramdeo KS; Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA.; Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA., Deshmukh SK; Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA.; Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA., Azim S; Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA.; Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA., Srivastava SK; Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA.; Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA., Singh S; Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA.; Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, USA., Singh AP; Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA.; Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, USA.
Jazyk:	angličtina
Zdroj:	EMBO reports [EMBO Rep] 2023 Mar 06; Vol. 24 (3), pp. e55643. Date of Electronic Publication: 2023 Jan 02.
DOI:	10.15252/embr.202255643
Abstrakt:	Extensive desmoplasia and poor vasculature renders pancreatic tumors severely hypoxic, contributing to their aggressiveness and therapy resistance. Here, we identify the HuR/MYB/HIF1α axis as a critical regulator of the metabolic plasticity and hypoxic survival of pancreatic cancer cells. HuR undergoes nuclear-to-cytoplasmic translocation under hypoxia and stabilizes MYB transcripts, while MYB transcriptionally upregulates HIF1α. Upon MYB silencing, pancreatic cancer cells fail to survive and adapt metabolically under hypoxia, despite forced overexpression of HIF1α. MYB induces the transcription of several HIF1α-regulated glycolytic genes by directly binding to their promoters, thus enhancing the recruitment of HIF1α to hypoxia-responsive elements through its interaction with p300-dependent histone acetylation. MYB-depleted pancreatic cancer cells exhibit a dramatic reduction in tumorigenic ability, glucose-uptake and metabolism in orthotopic mouse model, even after HIF1α restoration. Together, our findings reveal an essential role of MYB in metabolic reprogramming that supports pancreatic cancer cell survival under hypoxia. (© 2022 The Authors.)
Databáze:	MEDLINE
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