Post-translational SOX2 modification - a regulatory switch between self-renewal and differentiation in squamous cell carcinoma

总结 SOX 2是一种细胞命运决定转录因子，在约70%的皮肤和头颈部组织中表达。 鳞状细胞癌（SCC）患者。SOX 2在干细胞样肿瘤增殖细胞中高度富集 （TPC），其位于基底SCC层内，在那里它们可以自我更新或分化成基底上SCC层。 SCC细胞无增殖潜能。虽然我们知道SOX 2控制着TPC自我之间的命运选择， 尽管它的活性在鳞状细胞癌中是如何调节的， 调节机制可以发展成为癌症患者的治疗方法。在这里，我们建议测试 假设SOX 2的磷酸化抑制其活性，干扰SCC特异性SOX 2-PITX 1-PITX 2-PITX 1-PITX TP 63自我更新回路驱动克隆扩张和SCC生长，从而恢复KLF 4- SCC中依赖性鳞状细胞分化程序。我们的假设是基于我们的初步研究， 这表明SOX 2可以被磷酸化，并且这种磷酸化减弱了其在SCC中的活性， 细胞我们建议1）测试SOX 2磷酸化是否抑制TPC自我更新，克隆扩增和SCC。 生长; 2）鉴定调节SOX 2磷酸化和功能的激酶和磷酸酶;和3）定义 SOX 2活性控制TPC自我更新、SCC生长和分化的分子机制 在小鼠和患者来源的SCC模型中。我们希望我们提出的研究能解释 TPC自我更新和终末分化之间的分子水平，因此提供了新的概念 合理开发药理学方法，强制TPC承诺终末 分化成没有增殖潜力的SCC细胞。

SUMMARY SOX2 is a cell fate–determining transcription factor that is expressed in ~70% of cutaneous and head and neck squamous cell carcinomas (SCCs) in patients. SOX2 is highly enriched in stem cell–like tumor-propagating cells (TPCs), which are located within the basal SCC layer where they can self-renew or differentiate into suprabasal SCC cells without proliferative potential. Although we know SOX2 controls the fate choice between TPC self- renewal and squamous differentiation, it is unclear how its activity is regulated in SCCs and whether these regulatory mechanisms could be developed into therapies for cancer patients. Here, we propose to test the hypothesis that phosphorylation of SOX2 inhibits its activity, perturbs the SCC-specific SOX2-PITX1- TP63 self-renewal circuit that drives clonal expansion and SCC growth, and thereby restores the KLF4- dependent squamous differentiation program in SCCs. Our hypothesis is based on our preliminary studies, which showed that SOX2 can be phosphorylated and that this phosphorylation attenuates its activity in SCC cells. We propose to 1) test if SOX2 phosphorylation inhibits TPC self-renewal, clonal expansion, and SCC growth; 2) identify the kinases and phosphatases that regulate SOX2 phosphorylation and function; and 3) define the molecular mechanisms by which SOX2 activity governs TPC self-renewal, SCC growth, and differentiation in mouse and patient-derived SCC models. We expect our proposed research will explain the fate choice between TPC self-renewal and terminal differentiation on a molecular level and therefore provide new concepts for the rational development of pharmacological approaches that enforce the commitment of TPCs to terminally differentiate into SCC cells without proliferative potential.