Enhanced SREBP2-driven cholesterol biosynthesis by PKCl/i deficiency in epithelial intestinal cells promotes aggressive serrated tumorigenesis

The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection makes the identification of their metabolic requirements a priority. Here we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKC/ promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.

调节通过锯齿状途径引发和进展的侵袭性间充质结直肠癌（CRC）的代谢和信号通路尚在很大程度上未知。尽管作为BRAF突变癌已被相对充分地描述，但它们对当前靶向治疗的反应不佳、难以检测原位癌变以及内镜下切除的挑战性，使得识别其代谢需求成为优先事项。本研究展示了非典型蛋白激酶C（aPKC）、PKC/对SCAP的磷酸化促进了其降解并抑制了胆固醇生物合成的主要调节因子SREBP2的加工和激活。我们发现，通过降低aPKC水平而上调SREBP2和胆固醇对于控制小鼠和人类锯齿状肿瘤中的化生以及生成最侵袭性的细胞亚群至关重要。鉴于这些改变也在癌变之前被检测到，并且这些肿瘤对胆固醇代谢抑制剂的敏感性，我们的数据表明，针对胆固醇生物合成可能是锯齿状化学预防的潜在机制。