MYB and HIF1a crosstalk drives hypoxia-induced transcriptional reprogramming and adaptive signaling alterations in pancreatic cancer [RNA-seq]

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 HIF1a, 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 HIF1a in altered genomic occupancy of MYB. In addition, we examined the genomic distribution of HIF1a 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 HIF1a, and that MYB facilitates HIF1a binding to specific gene promoters. We also identify a subset of hypoxia-induced genes co-regulated by MYB and HIF1a, involved in oncogenic signaling pathways critical for hypoxic adaptation. These results highlight the reciprocal crosstalk between MYB and HIF1a, providing novel mechanistic insights into pancreatic cancer adaptation under hypoxia and suggesting MYB as a potential therapeutic target. Overall design: RNAseq profiling of MiaPaCa-2 Control cells cultured under normoxia (20% O2). RNAseq profiling of MiaPaCa-2 Control, MYB knockout (MYB KO) and HIF1a knockout (HIF1a KO) cells cultured under hypoxia (1% O2) conditions.