GLI activation by atypical protein kinase C ι/λ regulates the growth of basal cell carcinomas.
GLI activation by atypical protein kinase C ι/λ regulates the growth of basal cell carcinomas.
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基底细胞癌（BCC）的生长需要高水平的Hedgehog（Hh）信号通过转录因子Gli。虽然膜蛋白Smoothened（Smo）的抑制剂有效地抑制Hh信号传导，但早期肿瘤抗性说明需要额外的下游靶点用于治疗。在这里，我们将非典型蛋白激酶C iota/lambda（aPKC）确定为一种新型Gli调节因子。aPKC及其极性信号伴侣共定位于中心体，并与转移中缺失（MIM）形成复合物，MIM是一种增强Hh信号传导的支架蛋白。aPKC功能的遗传或药理学丧失阻断了Hh信号传导和BCC细胞的增殖。aPKC是Hh靶基因，与Gli形成正反馈环，并在BCC中表现出升高的水平。全基因组转录谱显示，aPKC和Smo控制肿瘤细胞中相似基因的表达。aPKC在Smo的下游起磷酸化和激活Gli 1的作用，导致最大的DNA结合和转录激活。活化的aPKC在Smo抑制剂抗性肿瘤中上调，靶向aPKC抑制抗性BCC细胞系的信号传导和生长。这些结果表明aPKC对于Hh依赖性过程是关键的，并且暗示aPKC是用于治疗Smo抑制剂抗性癌症的新的肿瘤选择性治疗靶点。
Basal cell carcinoma (BCC) growth requires high levels of Hedgehog (Hh) signaling through the transcription factor Gli. While inhibitors of membrane protein Smoothened (Smo) effectively suppress Hh signaling, early tumor resistance illustrates the need for additional downstream targets for therapy. Here we identify atypical Protein Kinase C iota/lambda (aPKC) as a novel Gli regulator. aPKC and its polarity signaling partners colocalize at the centrosome and form a complex with Missing-in-Metastasis (MIM), a scaffolding protein that potentiates Hh signaling. Genetic or pharmacological loss of aPKC function blocks Hh signaling and proliferation of BCC cells. aPKC is a Hh target gene that forms a positive feedback loop with Gli and exhibits elevated levels in BCCs. Genome-wide transcriptional profiling shows that aPKC and Smo control the expression of similar genes in tumor cells. aPKC functions downstream of Smo to phosphorylate and activate Gli1, resulting in maximal DNA binding and transcriptional activation. Activated aPKC is upregulated in Smo-inhibitor resistant tumors and targeting aPKC suppresses signaling and growth of resistant BCC cell lines. These results demonstrate aPKC is critical for Hh-dependent processes and implicates aPKC as a new, tumor-selective therapeutic target for the treatment of Smo-inhibitor resistant cancers.