Abstract 2351: MYB plays an essential role in the hypoxic survival of pancreatic cancer cells via its impact on metabolic reprogramming
Authors: Anand Shashi , Khan Mohammad Aslam , Zubair Haseeb , Sudan Sarabjeet Kour , Vikramdeo Kunwar Somesh , Deshmukh Sachin Kumar , Azim Shafquat , Srivastava Sanjeev Kumar , Singh Seema , Singh Ajay Pratap 
Published: June 2022

Pancreatic ductal adenocarcinoma exhibits high degree of intratumoral hypoxia due to its unique histopathological features contributing to its extremely aggressive nature and unusual chemoresistance. It is however not yet very clear what drives and sustains the growth of pancreatic cancer cells under an adverse hypoxic tumor microenvironment. Previously we reported that MYB was overexpressed in pancreatic cancer cells and supported the tumorigenicity and metastatic progression of pancreatic cancer cells. Here, we examined the role of MYB in hypoxic survival of pancreatic cancer cells. We found that the silencing of MYB expression in pancreatic cancer cells severely reduced their growth under hypoxia whereas its forced overexpression promoted hypoxic survival. We also observed that MYB was upregulated under hypoxia and its silencing was associated with a reduced accumulation of hypoxia inducible factor-1 α (HIF1α). Additionally, we confirmed HIF1α as a direct transcriptional target of MYB and its transcripts level and promoter activity correlated positively with MYB expression under both normoxia and hypoxia. Interestingly, restoration of HIF1α expression in MYB-silenced cells was not sufficient to rescue their survival under hypoxia. MYB knockdown pancreatic cancer cells failed to optimally reprogram their metabolism under hypoxia to meet their energetic and biosynthetic demands despite restored HIF1α overexpression. Specifically, MYB knockdown cells exhibited a large decrease in intracellular glucose and several metabolic intermediates of glycolysis, TCA cycle, and amino acid metabolism, whereas glycogenolysis and pentose phosphate pathway metabolites were increased. MYB silencing also altered the expression of several metabolic genes, including established hypoxia-responsive gene targets. MYB co-occupied the promoter regions of GLUT3, HK2, PFKL, ENO2, and MCT4 with HIF1α and its silencing reduced HIF1α binding to these promoters despite its forced overexpression. We also confirmed MYB interaction with HIF1α and p300 and demonstrated enhanced recruitment of p300 to these gene promoters in MYB-overexpressing pancreatic cancer cells. Altogether, our studies suggest that MYB acts as major regulator of metabolic reprogramming and HIF1α signaling and thus acts as an important driver of hypoxic survival of pancreatic cancer cells.

Citation Format: Shashi Anand, Mohammad Aslam Khan, Haseeb Zubair, Sarabjeet Kour Sudan, Kunwar Somesh Vikramdeo, Sachin Kumar Deshmukh, Shafquat Azim, Sanjeev Kumar Srivastava, Seema Singh, Ajay Pratap Singh. MYB plays an essential role in the hypoxic survival of pancreatic cancer cells via its impact on metabolic reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2351.