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MYB and HIF1α crosstalk drives hypoxia-induced transcriptional reprogramming and adaptive signaling alterations in pancreatic cancer [ChIP-seq]

ABSTRACT: Pancreatic cancer is an aggressive malignancy, characterized by extensive desmoplasia and a hypoxic tumor microenvironment that contributes to therapy resistance. MYB, a proto-oncogene encoding a transcription factor, plays a crucial role in pancreatic tumor growth, metastasis, and desmoplasia. Recently, we also revealed a role of MYB in hypoxic survival of pancreatic cancer by promoting metabolic reprogramming through interaction with HIF1α, modulating its expression and influencing its binding to glycolytic gene promoters. In this study, we examined the impact of hypoxia on the genome-wide occupancy of MYB by performing chromatin immunoprecipitation sequencing (ChIP-seq) analysis. We also used HIF1A knockout cells to investigate the role of HIF1α in altered genomic occupancy of MYB. In addition, we examined the genomic distribution of HIF1α in presence and absence of MYB and the impact of their crosstalk on transcriptional reprogramming and associated signaling alterations by RNA-seq and pathway analyses. Our findings show that hypoxia induces significant changes in MYB’s genomic distribution, partially dependent on HIF1α, and that MYB facilitates HIF1α binding to specific gene promoters. We also identify a subset of hypoxia-induced genes co-regulated by MYB and HIF1α, involved in oncogenic signaling pathways critical for hypoxic adaptation. These results highlight the reciprocal crosstalk between MYB and HIF1α, providing novel mechanistic insights into pancreatic cancer adaptation under hypoxia and suggesting MYB as a potential therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292665 | GEO | 2025/07/17

REPOSITORIES: GEO

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Project description:Published molecular profiling studies in patients with lymphoma suggested the influence of hypoxia inducible factor-1 alpha (HIF1α) targets in prognosis of DLBCL. Yet, the role of hypoxia in hematological malignancies remains unclear. We observed that activation of HIF1α resulted in global translation repression during hypoxic stress in DLBCL. Protein translation efficiency as measured using 35S-labeled methionine incorporation revealed a ≥50% reduction in translation upon activation of HIF1α. Importantly, translation was not completely inhibited and expression of clinically correlated hypoxia targets such as GLUT1, HK2, and CYT-C was found to be refractory to translational repression under hypoxia in DLBCL cells. Notably, hypoxic induction of these genes was not observed in normal primary B-cells. Translational repression was coupled with a decrease in mitochondrial function. Screening of primary DLBCL patient samples revealed that expression of HK2, which encodes for the enzyme hexokinase 2, was significantly correlated with DLBCL phenotype. Genetic knockdown studies demonstrated that HK2 is required for promoting growth of DLBCL under hypoxic stress. Altogether, our findings provide strong support for the direct contribution of HK2 in B-cell lymphoma development and suggest that HK2 is a key metabolic driver of the DLBCL phenotype.ne incorporation revealed a ≥50% reduction in translation upon activation of HIF1α. Importantly, translation was not completely blunted and expression of clinically correlated hypoxia targets such as GLUT1, HK2, and CYT-C was found to be refractory to translational repression under hypoxia in DLBCL cells. Notably, hypoxic induction of these genes was not observed in normal primary B-cells. Translational repression was coupled with decrease in mitochondrial function. Screening of DLBCL patient samples identified that expression of HK2, which encodes for the enzyme hexokinase 2, was significantly correlated with DLBCL phenotype. Genetic knockdown studies show that HK2 is required for promoting growth of DLBCL under hypoxic stress. Altogether, our findings provide more definitive proof of direct contribution of HK2 in development of B-cell lymphoma and suggest that HK2 is a key metabolic driver of DLBCL phenotype.

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MYB and HIF1α crosstalk drives hypoxia-induced transcriptional reprogramming and adaptive signaling alterations in pancreatic cancer [ChIP-seq]

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