Elevating SOX2 Downregulates MYC through a SOX2:MYC Signaling Axis and Induces a Slowly Cycling Proliferative State in Human Tumor Cells

Abstract

Slowly cycling/infrequently proliferating tumor cells present a clinical challenge due to their ability to evade treatment. Previous studies established that high levels of SOX2 in both fetal and tumor cells restrict cell proliferation and induce a slowly cycling state. However, the mechanisms through which elevated SOX2 levels inhibit tumor cell proliferation have not been identified. To identify common mechanisms through which SOX2 elevation restricts tumor cell proliferation, we initially performed RNA-seq using two diverse tumor cell types. SOX2 elevation in both cell types downregulated MYC target genes. Consistent with these findings, elevating SOX2 in five cell lines representing three different human cancer types decreased MYC expression. Importantly, the expression of a dominant-negative MYC variant, omomyc, recapitulated many of the effects of SOX2 on proliferation, cell cycle, gene expression, and biosynthetic activity. We also demonstrated that rescuing MYC activity in the context of elevated SOX2 induces cell death, indicating that the downregulation of MYC is a critical mechanistic step necessary to maintain survival in the slowly cycling state induced by elevated SOX2. Altogether, our findings uncover a novel SOX2:MYC signaling axis and provide important insights into the molecular mechanisms through which SOX2 elevation induces a slowly cycling proliferative state.

Enhancing Sox/Oct cooperativity induces higher-grade developmental reset

“…Mouse remains the only species for which generation of all-iPSCs animals has been reported 122–124 ; and germline competence has been reported only for mouse and male rat 125 , highlighting the limitations of today’s technologies. Naïve PSCs have lower Myc levels compared to primed cells 97,99 , which could be a direct effect of high levels of Sox2 126 in naïve cells (Fig. 6e).…”

CXCR2 inhibition overcomes ponatinib intolerance by eradicating chronic myeloid leukemic stem cells through PI3K/Akt/mTOR and dipeptidylpeptidase Ⅳ (CD26)

“…Notably, CML LSCs are highly sensitive to alterations in c-Myc expression, which is required for the maintenance of CML leukemia-initiating cells [ 57 , 58 ]. Although the relationship between c-Myc and SOX2 in cancer cells remains unclear, some studies suggest that they co-localize within a protein complex [ 59 , 60 ]. Specifically, c-Myc has been shown to regulate the expression of the SOX2 gene in breast cancer-derived CSCs [ 61 ], implying that c-Myc may modulate the expression of other transcription markers to regulate cancer stemness.…”

Expression and Functional Analysis of core stemness factors OSKM (OCT4, SOX2, KLF4, and MYC) in Pan-cancer

“…[18][19][20] Considering about 20% of mice offspring derived from iPSCs were found to develop tumors, it was questioned that the attributes of so-called stem cell is more like those of tumor cells and MYC, KLF4 genes might be carcinogenic. [21] Even though more and more studies indicated that the stem cell transcription factors play important roles in maintaining the self-renewal, reprogramming and multiple differentiations of tumor cells, [22,23] how OSKM genes participate in these processes still needs to be further explored.…”