Abstract：
The urea cycle is frequently rewired in cancer cells to meet the metabolic demands of cancer. Elucidation of the underlying mechanism by which oncogenic signaling mediates urea cycle reprogramming could help identify targetable metabolic vulnerabilities. In this study, we discovered that oncogenic activation of KRAS in non-small cell lung cancer (NSCLC) silenced the expression of argininosuccinate synthase 1 (ASS1), a urea cycle enzyme that catalyzes the production of arginine from aspartate and citrulline, and thereby diverted the utilization of aspartate to pyrimidine synthesis to meet the high demand for DNA replication. Specifically, KRAS signaling facilitated a hypoacetylated state in the promoter region of the ASS1 gene in a histone deacetylase 3-dependent manner, which in turn impeded the recruitment of c-MYC for ASS1 transcription. ASS1 suppression in KRAS-mutant NSCLC cells impaired the biosynthesis of arginine and rendered a dependency on the arginine transmembrane transporter SLC7A1 to import extracellular arginine. Depletion of SLC7A1 in both patient-derived organoid and xenograft models inhibited KRAS-driven NSCLC growth. Together, these findings uncover the role of oncogenic KRAS in rewiring urea cycle metabolism and identify SLC7A1-mediated arginine uptake as a therapeutic vulnerability for treating KRAS-mutant NSCLC.
UNASSIGNED: ASS1 deficiency is induced by mutant KRAS in NSCLC to facilitate DNA synthesis and creates a dependency on SLC7A1, revealing dietary arginine restriction and SLC7A1 inhibition as potential therapeutic strategies.
UNASSIGNED: ASS1 deficiency is induced by mutant KRAS in NSCLC to facilitate DNA synthesis and creates a dependency on SLC7A1, revealing dietary arginine restriction and SLC7A1 inhibition as potential therapeutic strategies.
摘要：
尿素循环经常在癌细胞中重新连接以满足癌症的代谢需求。阐明致癌信号介导尿素循环重编程的潜在机制可以帮助识别可靶向的代谢脆弱性。在这项研究中,我们发现KRAS在非小细胞肺癌（NSCLC）中的致癌激活沉默了精氨酸琥珀酸合酶1（ASS1）的表达，一种尿素循环酶，催化天冬氨酸和瓜氨酸产生精氨酸，从而将天冬氨酸的利用转向嘧啶合成，以满足对DNA复制的高需求。具体来说,KRAS信号以组蛋白去乙酰化酶3依赖性方式促进ASS1基因启动子区域的低乙酰化状态，这反过来又阻碍了ASS1转录中c-MYC的募集。KRAS突变型NSCLC细胞中的ASS1抑制损害了精氨酸的生物合成，并依赖精氨酸跨膜转运蛋白SLC7A1输入细胞外精氨酸。在患者来源的类器官和异种移植模型中SLC7A1的耗尽抑制了KRAS驱动的NSCLC生长。一起,这些发现揭示了致癌KRAS在重新连接尿素循环代谢中的作用,并确定了SLC7A1介导的精氨酸摄取是治疗KRAS突变型NSCLC的治疗脆弱性.
■ASS1缺陷是由突变KRAS在NSCLC中诱导的，以促进DNA合成，并产生对SLC7A1的依赖性，这表明饮食精氨酸限制和SLC7A1抑制是潜在的治疗策略。
■ASS1缺陷是由突变KRAS在NSCLC中诱导的，以促进DNA合成，并产生对SLC7A1的依赖性，这表明饮食精氨酸限制和SLC7A1抑制是潜在的治疗策略。
