American Association for Cancer Research, Molecular Cancer Research, 10_Supplement(13), p. PR14-PR14, 2015
DOI: 10.1158/1557-3125.myc15-pr14
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Abstract Numerous studies report that both hematopoietic and some solid tumors are organized in a hierarchical manner where tumor growth is driven by a small subset of cancer stem cells (CSCs). However, the distinct molecular identity of CSC versus non-CSC is not yet clearly known, which limit our understanding on how CSC self-renewal pathways operate to drive tumorigenicity. Here, we report that MYC and HIF-2alpha co-operate to maintain distinct identity and self-renewal capacity of CSCs. In a transgenic mouse model of conditional MYC driven thymic lymphoma, we identified a Sca-1+ cell population that showed tumor stemness (self-renewal and undifferentiation state) phenotype, including high expression of Nanog, Sox2 and HIF-2alpha. When injected to congenic mice, Sca-1+ cells but not Sca-1- cells exhibited hierarchical organization including self-renewal capacity. ChIP assay revealed direct MYC binding of HIF-2alpha promoter region in Sca-1+ but not in the Sca-1- cells. Inhibition of HIF-2alpha led to increase ROS generation, decrease of GSH synthesis, differentiation, and loss of self-renewal capacity of Sca-1+ cells. In contrast, inhibition of HIF-2alpha had no phenotypic effect on Sca-1- cells. Thus, we have identified a distinct CSC population in MYC dependent cancer cells, where MYC preferentially binds to HIF-2alpha to maintain self-renewal capacity. Citation Format: Bikul Das, Bikul Das, Hong Li, Hong Li, Rashmi Bhuyan, Dean W. Felsher. HIF-2alpha regulates self-renewal of MYC dependent cancer stem cells. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr PR14.