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

Overview
Journal Cancers (Basel)
Publisher MDPI
Specialty Oncology
Date 2022 Apr 23
PMID 35454854
Authors
Affiliations
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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.

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References
1.
Dhimolea E, De Matos Simoes R, Kansara D, AlKhafaji A, Bouyssou J, Weng X . An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence. Cancer Cell. 2021; 39(2):240-256.e11. PMC: 8670073. DOI: 10.1016/j.ccell.2020.12.002. View

2.
Metz E, Wilder P, Dong J, Datta K, Rizzino A . Elevating SOX2 in prostate tumor cells upregulates expression of neuroendocrine genes, but does not reduce the inhibitory effects of enzalutamide. J Cell Physiol. 2019; 235(4):3731-3740. PMC: 6961844. DOI: 10.1002/jcp.29267. View

3.
Chew J, Loh Y, Zhang W, Chen X, Tam W, Yeap L . Reciprocal transcriptional regulation of Pou5f1 and Sox2 via the Oct4/Sox2 complex in embryonic stem cells. Mol Cell Biol. 2005; 25(14):6031-46. PMC: 1168830. DOI: 10.1128/MCB.25.14.6031-6046.2005. View

4.
Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

5.
Metz E, Rizzino A . Sox2 dosage: A critical determinant in the functions of Sox2 in both normal and tumor cells. J Cell Physiol. 2019; 234(11):19298-19306. PMC: 6662612. DOI: 10.1002/jcp.28610. View