Plakophilin 1 enhances MYC expression to promote squamous cell lung cancer

Plakophilin 1 (PKP1) is a component of desmosomes. Although desmosome function loss has been associated with increased cell migration and pro-oncogenic activity, we previously observed PKP1 overexpression in squamous cell lung cancer (SqCLC). We developed in vitro and in vivo functional models of PKP1 gain/loss in SqCLC to explore this paradox. Greater cell dissemination but reduced cell proliferation was observed in CRISPR-Cas9 PKP1-knockout clones. PKP1 expression promoted cell proliferation, cell survival, and in vivo xenograft engraftment, and these pro-oncogenic activities were mediated by the functional relationship of PKP1 with MYC. PKP1 bound to the 5’UTR of MYC mRNA, enhancing MYC translation, and MYC bound directly to the PKP1 promoter, enhancing PKP1 transcription. We propose PKP1 as a novel oncogene in SqCLC and a post-transcriptional regulator of MYC. PKP1 may be a valuable diagnostic biomarker and potential therapeutic target for SqCLC. Importantly, PKP1 inhibition may indirectly target MYC, a primary anti-cancer target. 4 non-paired samples were analyzed (2 controls and 2 treated)

桥粒斑蛋白1（Plakophilin 1, PKP1）是桥粒的组成成分之一。尽管桥粒功能缺失已被证实与细胞迁移增强及促癌活性升高相关，但我们此前在肺鳞状细胞癌（SqCLC）中观察到PKP1的过表达现象。为探究这一矛盾现象，我们构建了肺鳞状细胞癌中PKP1表达增减的体外与体内功能模型。在CRISPR-Cas9介导的PKP1敲除克隆中，我们观察到细胞播散能力增强但细胞增殖能力减弱。PKP1的表达可促进细胞增殖、细胞存活及体内异种移植定植，而这些促癌活性均通过PKP1与MYC的相互作用介导。PKP1可结合MYC mRNA的5'非翻译区（5’UTR），增强MYC的翻译过程；同时MYC可直接结合PKP1的启动子区域，促进PKP1的转录。我们提出PKP1可作为肺鳞状细胞癌中一种新型癌基因，同时也是MYC的转录后调控因子。PKP1有望成为肺鳞状细胞癌极具价值的诊断生物标志物与潜在治疗靶点。尤为关键的是，抑制PKP1可间接靶向MYC这一核心抗癌靶点。本研究共分析了4份非配对样本（2份对照组与2份处理组）。