Elevating SOX2 downregulates MYC through a SOX2:MYC signaling axis and induces a slowly cycling proliferative state in human tumor cells

ABSTRACT: Quiescent/slowly circling tumor cells present a clinical challenge due to their ability to evade treatement. Recent studies have demonstrated that quiescent/slow circling tumor cells hijack embryonic growth arrest mechanisms and consequently resist chemotherapy. Significantly, earlier 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 performed RNA-seq using ONS76 medulloblastoma and LNCaP prostate tumor cells engineered to express SOX2 from an inducible promoter. SOX2 elevation in both cell lines significantly downregulated MYC target genes. Consistent with these findings, elevating SOX2 in five cell lines representing three different human cancer types decreases MYC mRNA and protein levels. Importantly, the expression of a dominant-negative MYC variant, omomyc, recapitulated many of the effects of SOX2 on proliferation, cell cycle, and gene expression. As predicted by our Gene Ontology analysis, elevating SOX2 decreases biosynthetic activity, in particular protein translation. We also demonstrate 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 novel insights into the molecular mechanisms through which SOX2 elevation induces a slowly cycling proliferative state.

ORGANISM(S): Homo sapiens

PROVIDER: GSE190936 | GEO | 2022/08/03

REPOSITORIES: GEO