SOX9 indirectly regulates CEACAM1 expression and immune resistance in melanoma cells.
SOX9 indirectly regulates CEACAM1 expression and immune resistance in melanoma cells.
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DOI：
10.18632/oncotarget.7379
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发表时间：
2016-05-24
期刊：
影响因子：
--
通讯作者：
Markel G
中科院分区：
文献类型：
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作者：
Ashkenazi S;Ortenberg R;Besser M;Schachter J;Markel G
由于黑色素瘤细胞具有免疫原性，它们会引发适应性免疫反应并产生抗肿瘤t细胞。这种相互作用的核心因素是CEACAM1（癌胚抗原细胞粘附分子1），这是一种跨膜糖蛋白，先前在我们的实验室中被证明可以保护黑色素瘤细胞免受T细胞介导的杀伤。在这项研究中，我们研究了转录因子SOX9在黑色素瘤细胞CEACAM1表达和免疫抵抗调控中的作用。内源性SOX9的下调导致CEACAM1的上调，而其过表达则导致相反的效果。我们发现SOX9在转录水平上控制CEACAM1的表达，但以间接的方式，因为即使所有八个潜在的SOX9结合位点都被取消，CEACAM1启动子的调控仍然完整。一系列的启动子截断将sox9控制区域定位到启动子的近200bp。Sp1和ETS1结合位点的点突变确定了这些转录因子是主要的sox9控制的介质。共同免疫沉淀研究表明，SOX9和Sp1在黑色素瘤细胞中物理相互作用，而SOX9的沉默下调了同一细胞中的ETS1，而不是Sp1。最后，SOX9的敲低确实使黑色素瘤细胞抵抗T细胞介导的杀伤，这与CEACAM1表达增加一致。总之，我们发现SOX9调节黑色素瘤细胞中CEACAM1的表达，从而调节其免疫抗性。由于CEACAM1是黑色素瘤生物学和免疫串扰的关键蛋白，进一步了解其调控可以提供新的见解，并有助于开发新的治疗方法。
As melanoma cells are immunogenic, they instigate an adaptive immune response and production of anti-tumor T-cells. A central factor in this interaction is CEACAM1 (carcinoembryonic antigen cell adhesion molecule 1), a transmembrane glycoprotein previously shown in our lab to protect melanoma cells from T cell-mediated killing. In this study, we examine the role of transcription factor SOX9 in the regulation of CEACAM1 expression and immune resistance in melanoma cells. Knockdown of endogenous SOX9 results in CEACAM1 up-regulation, while its overexpression leads to the opposite effect. We show that SOX9 controls CEACAM1 expression at a transcriptional level, but in an indirect manner, as regulation of the CEACAM1 promoter remains intact even when all eight potential SOX9-binding sites are abolished. A series of promoter truncations localizes the SOX9-controlled area to the proximal 200bp of the promoter. Point mutations in putative Sp1 and ETS1 binding sites identify these transcription factors as the primary SOX9-controlled mediators. Co-immunoprecipitation studies show that SOX9 and Sp1 physically interact in melanoma cells, while silencing of SOX9 down-regulates ETS1, but not Sp1, in the same cells. Finally, knockdown of SOX9 indeed renders melanoma cells resistant to T cell-mediated killing, in line with the increased CEACAM1 expression. In conclusion, we show that SOX9 regulates CEACAM1 expression in melanoma cells, and thereby their immune resistance. As CEACAM1 is a pivotal protein in melanoma biology and immune crosstalk, further understanding of its regulation can provide new insights and contribute to the development of novel approaches to therapy.
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