MYCRegulates theHIF2αStemness Pathway viaNanogandSox2to Maintain Self-Renewal in Cancer Stem Cells versus Non-Stem Cancer Cells

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 þ CSCs versus Sca-1 À non-CSCs. MYC preferentially bound to the promoter and activated hypoxia-inducible factor-2a (HIF2a) in Sca-1 þ cells only. Furthermore, the reprogramming factors, Nanog and Sox2, facilitated MYC regulation of HIF2a in Sca-1 þ versus Sca-1 À cells. Reduced expression of HIF2a inhibited the self-renewal of Sca-1 þ cells; this effect was blocked through suppression of ROS by N-acetyl cysteine or the knockdown of p53, Nanog, or Sox2. Similar results were seen in ABCG2 þ CSCs versus ABCG2 À 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 HIF2a stemness pathway. Identification of this stemness pathway as a unique CSC determinant may have significant therapeutic implications.

Coronavirus activates a stem cell-mediated defense mechanism that reactivates dormant tuberculosis: implications in COVID-19 pandemic

“…Briefly, when a clone of stem cells such as hESCs cell colony is threatened by hypoxia/oxidative stress induced differentiation/apoptosis, a few of these cells reprogram to an "enhanced stemness" phenotype. This phenotype is characterized by distinct gene expression associated with HIF-2alpha stemness pathway (26,31), and rapid expansion of the reprogrammed cells. These cells continue to maintain enhanced stemness phenotype for the next two weeks, and then activate p53 to undergo was not certified by peer review) is the author/funder.…”

Cancer Stem Cells in Pheochromocytoma and Paraganglioma

“…Increasing evidence suggests that CSCs are reliant on low oxygen conditions, and therefore on HIF1α and HIF2α to maintain their stem cell features (47,60). Recently, it was shown that only in CSCs the pluripotencypromoting transcription factors NANOG and SOX2 cooperate with MYC to regulate HIF2α, which leads to a decrease in P53 expression and reduces the levels of reactive oxygen species in CSCs thereby promoting stemness (61). This is supported by other studies showing that primarily HIF2α is activated in CSCs (62).…”

Hypoxia Inducible Factors’ Signaling in Pediatric High-Grade Gliomas: Role, Modelization and Innovative Targeted Approaches

“…Indeed, the unique inhibition of HIF-2α, but not HIF-1α, was sufficient to decrease cell proliferation in MYC amplified cells, suggesting a complex transcriptional synergy between HIF-1α and HIF-2α. MYC seems also to maintain self-renewal exclusively in pHGG stem cells by selective binding to the HIF-2α promoter and the activation of the HIF-2α stemness pathway [58]. The balanced expression of HIF-1α/HIF-2α probably is one of the key drivers of pHGG cell survival and renewal concomitantly to a high level of Oct4 or CD133+ cells [40,58].…”

“…MYC seems also to maintain selfrenewal exclusively in pHGG stem cells by selective binding to the HIF-2α promoter and the activation of the HIF-2α stemness pathway [58]. The balanced expression of HIF-1α/HIF-2α probably is one of the key drivers of pHGG cell survival and renewal concomitantly to a high level of Oct4 or CD133+ cells [40,58]. For cell homeostasis, in addition to the glycolytic switch, the mitochondrial oxidative phosphorylation system (OxPHOS) usually appears when Warburg effect decreases during tumor reoxygenation, and promotes a smaller pHGG cell viability [56] (Figure 3).…”