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.

侵袭性间质表型结直肠癌（colorectal cancer, CRC）通过锯齿状途径发生与进展，其调控代谢与信号通路目前尚未被完全阐明。尽管这类肿瘤作为BRAF突变型肿瘤已有相对充分的特征鉴定，但它们对当前靶向治疗应答不佳、癌前病变检测困难，且内镜下切除极具挑战性，因此明确其代谢依赖已成为首要研究方向。本研究证实，非典型蛋白激酶C（atypical PKC, aPKC）的PKCλ/ι亚型可对固醇调节元件结合蛋白裂解激活蛋白（SCAP）进行磷酸化修饰，进而促进SCAP的降解，并抑制胆固醇生物合成的核心调控因子——固醇调节元件结合蛋白2（SREBP2）的加工与激活。我们发现，降低aPKC水平可上调SREBP2表达及胆固醇含量，这对于调控上皮化生过程，并在小鼠及人类的锯齿状肿瘤中生成侵袭性最强的细胞亚群至关重要。鉴于这些改变可在肿瘤发生前被检测到，且这类肿瘤对胆固醇代谢抑制剂具有敏感性，我们的研究结果表明，靶向抑制胆固醇生物合成或可成为锯齿状肿瘤化学预防的潜在策略。