Elevating SOX2 Downregulates MYC through a SOX2:MYC Signaling Axis and Induces a Slowly Cycling Proliferative State in Human Tumor Cells.
Elevating SOX2 Downregulates MYC through a SOX2:MYC Signaling Axis and Induces a Slowly Cycling Proliferative State in Human Tumor Cells.
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缓慢循环/不频繁增殖的肿瘤细胞逃避以积极增殖的肿瘤细胞为靶点的治疗的能力是一个主要的临床挑战。先前的研究证实，胎儿和肿瘤细胞中SOX2的高水平限制了细胞的增殖，并诱导了缓慢的周期状态。然而，SOX2水平升高抑制肿瘤细胞增殖的机制尚未确定。本文介绍的研究旨在确定SOX2升高限制肿瘤细胞增殖的机制。我们发现SOX2的升高降低了MYC和MYC靶基因的表达。我们还确定，下调MYC是维持SOX2升高诱导的缓慢循环状态下生存所必需的关键机制步骤。总之，我们的研究揭示了一个新的SOX2：MYC信号轴，并为SOX2上调诱导缓慢循环的增殖状态的分子机制提供了重要的见解。缓慢周期/不频繁增殖的肿瘤细胞由于其逃避治疗的能力而成为临床上的一个挑战。先前的研究证实，胎儿和肿瘤细胞中SOX2的高水平限制了细胞的增殖，并诱导了缓慢的周期状态。然而，SOX2水平升高抑制肿瘤细胞增殖的机制尚未确定。为了确定SOX2升高限制肿瘤细胞增殖的共同机制，我们最初使用两种不同的肿瘤细胞类型进行了RNA-SEQ。SOX2在两种细胞类型中的升高下调了MYC靶基因。与这些发现一致的是，在代表三种不同人类癌症类型的五种细胞系中，SOX2的升高降低了MYC的表达。重要的是，显性负MYC变异体Oomyc的表达概括了SOX2对细胞增殖、细胞周期、基因表达和生物合成活性的许多影响。我们还证明了在SOX2升高的背景下拯救MYC活性会导致细胞死亡，这表明下调MYC是维持SOX2升高诱导的缓慢循环状态下生存所必需的关键机制步骤。总之，我们的发现揭示了一个新的SOX2：MYC信号轴，并为SOX2升高诱导缓慢循环的增殖状态的分子机制提供了重要的见解。
The ability of slowly cycling/infrequently proliferating tumor cells to evade treatment with therapies that target actively proliferating tumor cells represents a major clinical challenge. 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. The studies presented here set out to determine the mechanisms through which SOX2 elevation restricts tumor cell proliferation. We demonstrated that elevating SOX2 decreases the expression of MYC and MYC target genes. We also determined 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 studies 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. 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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