PDF(Pubmed)
Abstract：
SCAP plays a central role in controlling lipid homeostasis by activating SREBP-1, a master transcription factor in controlling fatty acid (FA) synthesis. However, how SCAP expression is regulated in human cancer cells remains unknown. Here, we revealed that STAT3 binds to the promoter of SCAP to activate its expression across multiple cancer cell types. Moreover, we identified that STAT3 also concurrently interacts with the promoter of SREBF1 gene (encoding SREBP-1), amplifying its expression. This dual action by STAT3 collaboratively heightens FA synthesis. Pharmacological inhibition of STAT3 significantly reduces the levels of unsaturated FAs and phospholipids bearing unsaturated FA chains by reducing the SCAP-SREBP-1 signaling axis and its downstream effector SCD1. Examination of clinical samples from patients with glioblastoma, the most lethal brain tumor, demonstrates a substantial co-expression of STAT3, SCAP, SREBP-1, and SCD1. These findings unveil STAT3 directly regulates the expression of SCAP and SREBP-1 to promote FA synthesis, ultimately fueling tumor progression.
摘要：
SCAP通过激活SREBP-1（控制脂肪酸（FA）合成的主要转录因子）在控制脂质稳态中起着核心作用。然而,SCAP在人类癌细胞中的表达是如何被调控的仍然是未知的。这里,我们发现STAT3与SCAP的启动子结合以激活其在多种癌细胞类型中的表达.此外，我们发现STAT3也同时与SREBF1基因（编码SREBP-1）的启动子相互作用，放大它的表达。STAT3的这种双重作用协同提高了FA合成。STAT3的药理学抑制通过降低SCAP-SREBP-1信号轴及其下游效应子SCD1显著降低不饱和FA和携带不饱和FA链的磷脂的水平。检查胶质母细胞瘤患者的临床样本，最致命的脑肿瘤,证明STAT3、SCAP、SREBP-1和SCD1。这些发现揭示了STAT3直接调节SCAP和SREBP-1的表达以促进FA合成,最终推动肿瘤进展。
