Dysregulated metabolism contributes to cancer initiation and progression, but the key drivers of these pathways are just being discovered. Here, we report a critical role for proline catabolism in non-small cell lung cancer (NSCLC). Proline dehydrogenase (PRODH) is activated to reduce proline levels by the chromatin remodeling factor lymphoid-specific helicase (LSH), an epigenetic driver of NSCLC. PRODH promotes NSCLC tumorigenesis by inducing epithelial to mesenchymal transition (EMT) and IKKα-dependent inflammatory genes, including CXCL1, LCN2, and IL17C. Consistently, proline addition promotes the expression of these inflammatory genes, as well as EMT, tumor cell proliferation, and migration in vitro and tumor growth in vivo, while the depletion or inhibition of PRODH blocks these phenotypes. In summary, we reveal an essential metabolic pathway amenable to targeting in NSCLC.

代谢失调有助于癌症的发生和发展，但这些途径的关键驱动因素才刚刚被发现。在这里，我们报告了脯氨酸分解代谢在非小细胞肺癌 (NSCLC) 中的关键作用。脯氨酸脱氢酶 (PRODH) 被染色质重塑因子淋巴特异性解旋酶 (LSH) 激活以降低脯氨酸水平，LSH 是 NSCLC 的表观遗传驱动因素。PRODH 通过诱导上皮间质转化 (EMT) 和 IKKα 依赖性炎症基因（包括CXCL1、LCN2和IL17C ）促进 NSCLC 肿瘤发生. 一致地，脯氨酸添加促进这些炎症基因的表达，以及 EMT、肿瘤细胞增殖和体外迁移和体内肿瘤生长，而 PRODH 的消耗或抑制阻断了这些表型。总之，我们揭示了一种适合靶向 NSCLC 的重要代谢途径。