MYC regulates the HIF-2alpha stemness pathway via Nanog and Sox2 to maintain self-renewal in cancer stem cells versus non-stem cancer cells. Cancer research Das, B., Pal, B., Bhuyan, R., Li, H., Sarma, A., Gayan, S., Talukdar, J., Sandhya, S., Bhuyan, S., Gogoi, G., Gouw, A. M., Baishya, D., Gotlib, J. R., Kataki, A. C., Felsher, D. W. 2019

Abstract

Cancer stem cells (CSC) maintain both undifferentiated self-renewing CSCs and differentiated, non-self-renewing non-CSCs through cellular division. However, molecular mechanisms that maintain self-renewal in CSCs versus non-CSCs are not yet clear. Here, we report that in a transgenic mouse model of MYC-induced T cell leukemia, MYC maintains self-renewal in Sca1+ CSCs versus Sca-1- non-CSCs. MYC preferentially bound to the promoter and activated HIF-2alpha in Sca-1+ cells only. Further, the reprogramming factors Nanog and Sox2 facilitated MYC regulation of HIF-2alpha in Sca-1+ versus Sca-1- cells. Reduced expression of HIF-2alpha inhibited the self-renewal of Sca-1+ cells; this effect was blocked through suppression of reactive oxygen species (ROS) by N-acetyl cysteine (NAC) or the knock down of p53, Nanog or Sox2. Similar results were seen in ABCG2+ CSCs versus ABCG2- non-CSCs from primary human T cell lymphoma. Thus, MYC maintains self-renewal exclusively in CSCs by selectively binding to the promoter and activating the HIF-2alpha stemness pathway. Identification of this stemness pathway as a unique CSC determinant may have significant therapeutic implications.

View details for DOI 10.1158/0008-5472.CAN-18-2847

View details for PubMedID 31266772