SCML2选择性自噬降解异常调控染色质重塑促进鼻咽癌放疗耐受及其分子机制

放射治疗是鼻咽癌患者的首选，但仍有20%的中晚期患者对放疗耐受，迫切需要新的治疗手段。我们模拟临床放射治疗方式构建了鼻咽癌放疗耐受的细胞模型，通过全蛋白质谱及免疫印迹等方法发现放疗抵抗细胞自噬能力下降，染色质重塑相关SCML2蛋白及其苏木化水平上调，H2AK119单泛素化水平下调；阻断自噬发生可见SCML2蛋白明显上调，干扰SCML2则会抑制放疗抵抗细胞的恶性表型。本课题拟在放疗耐受的细胞模型上，探究自噬缺陷在放疗抵抗中的作用，阐明SCML2蛋白选择性自噬降解异常的分子机制，明确其在放疗耐受细胞中高表达的原因；阐明其发生苏木化修饰入核后，通过与PRC1复合体相互作用，抑制H2AK119单泛素化水平，进而重塑染色质使细胞表达出特定的基因谱，导致细胞对放疗产生抵抗的分子机制；在放疗耐受的鼻咽癌细胞和小鼠模型上明确靶向干预SCML2对放疗抵抗的逆转作用，为放疗耐受提供潜在靶标和可能的新治疗策略。

Radiotherapy is the preferred treatment for nasopharyngeal carcinoma. However, 20% of patients with advanced nasopharyngeal carcinoma are resistant to radiotherapy. Therefore, novel therapeutic strategies for nasopharyngeal carcinoma are urgently needed. In our preliminary study, we constructed radioresistant cell models following clinical radiotherapy. By using whole proteome mass spectra and immunoblots, we found that the autophagic flux was blocked. Moreover, both total SCML2 protein which was related to chromatin remodeling and its SUMOylated form were found to be up-regulated, coinciding with downregulation of ubiquitination on H2AK119. Intriguingly, SCML2 was significantly up-regulated by blocking autophagy, and the malignant phenotypes of radioresistant cells was restricted with knockdown of SCML2. In this proposal, we will explore, based on our novel radioresistant cell model, the role of autophagy deficiency in radiotherapy resistance, clarify the molecular mechanism of selective autophagic degradation of SCML2 protein, and pinpoint the causes for its high expression in radiotherapy-resistant cells. We aim to clarify the molecular mechanism which SUMOylated SCML2 interacts with PRC1 complex in the nucleus to inhibit the ubiquitination of H2AK119, and thereby remodels the chromatin to generate specific gene expression profiles and render the tumor cells resistance to radiotherapy. It will be tested that targeting SCML2 in radiotherapy-resistant nasopharyngeal carcinoma cells and mouse models can reverse the radiotherapy resistance phenotype, which will provide potential targets and possible new therapeutic strategies for radiotherapy resistant patients.