SOX2-MYC Axis: Transcriptional Repression of the MYC Oncogene by SOX2

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ABSTRACT A wide array of strategies and small molecule inhibitors have been identified that target actively proliferating tumor cells. However, quiescent tumor cells are largely resistant to conventional therapies used to eliminate proliferating tumor cells. Hence, quiescent tumor cells pose a major clinical challenge and a significant unmet need in the treatment of cancer, because quiescent cells represent a residual population of tumor cells that can drive tumor recurrence. To address this unmet need, we have been studying the transcription factor SOX2, whose elevated expression has been shown to restrict the proliferation of many different tumor cell types as well as the proliferation of normal fetal stem cells. Our work has established that elevating SOX2 from an inducible promoter in multiple tumor cell types invariably leads to growth inhibition. Moreover, we determined that elevating SOX2 in vivo leads to a reversible state of tumor growth arrest, where tumor growth resumes when SOX2 returns to endogenous levels. To determine how SOX2 restricts tumor cell growth, we examined how elevating SOX2 alters the transcriptome in different tumor cell types. These studies demonstrated that elevation of SOX2 downregulates MYC expression and the expression of MYC target genes. To extend these findings, we performed a MYC rescue study and determined that failure to downregulate MYC when SOX2 is elevated is deleterious to the cells. Thus, this newly discovered SOX2:MYC axis appears to play a critical role in growth inhibition when SOX2 is elevated. Equally important, we determined that elevating SOX2 downregulates MYC at the transcriptional level. The studies proposed here seek to determine how elevating SOX2 decreases MYC transcription. In proliferating cells, MYC transcription is dependent on multiple distal enhancers that activate the MYC promoter via chromatin loops whose formation is dependent on the binding of β-catenin to Wnt Response Elements (WREs) present in each MYC enhancer. Importantly, SOX2 has been shown to interfere with Wnt signaling by its interaction with β-catenin via the R1 transactivation domain of SOX2, which we recently determined is required to inhibit tumor cell growth and downregulate MYC. Based on these findings, we hypothesize that elevating SOX2 downregulates MYC expression by interfering with the function of transcription factors that promote the formation of critical long-range enhancer-promoter interactions required to drive MYC transcription. This hypothesis will be tested by two Specific Aims. Aim 1 will determine how elevating SOX2 alters the 3-D chromatin structure of the MYC locus. Aim 2 will determine whether elevating SOX2 alters the binding of transcription factors to MYC enhancers, changes histone modifications found at active MYC enhancers, and/or blocks the formation of the transcription preinitiation complex at the MYC promoter. Understanding how elevating SOX2 downregulates MYC would be highly significant, because little is known about the links between these two master regulators. Ultimately, we believe our studies will lead to the discovery of novel druggable targets to eradicate quiescent tumor cells implicated in cancer recurrence.