Department of Medicine, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, 21201, USA.
Department of Veteran Affairs, Maryland Healthcare System, Baltimore, MD 21201, USA.
Nat Commun. 2018 Feb 26;9(1):829. doi: 10.1038/s41467-018-03028-y.
Altered lipid metabolism and aberrant protein translation are strongly associated with cancerous outgrowth; however, the inter-regulation of these key processes is still underexplored in diffuse large B-cell lymphoma (DLBCL). Although fatty acid synthase (FASN) activity is reported to positively correlate with PI3K-Akt-mTOR pathway that can modulate protein synthesis, the precise impact of FASN inhibition on this process is still unknown. Herein, we demonstrate that attenuating FASN expression or its activity significantly reduces eIF4B (eukaryotic initiation factor 4B) levels and consequently overall protein translation. Through biochemical studies, we identified eIF4B as a bonafide substrate of USP11, which stabilizes and enhances eIF4B activity. Employing both pharmacological and genetic approaches, we establish that FASN-induced PI3K-S6Kinase signaling phosphorylates USP11 enhancing its interaction with eIF4B and thereby promoting oncogenic translation.
脂质代谢和蛋白质翻译的改变与癌症的生长密切相关；然而，在弥漫性大 B 细胞淋巴瘤（DLBCL）中，这些关键过程的相互调节仍未得到充分探索。尽管脂肪酸合酶（FASN）的活性与可以调节蛋白质合成的 PI3K-Akt-mTOR 途径呈正相关，但 FASN 抑制对该过程的确切影响尚不清楚。在此，我们证明抑制 FASN 的表达或其活性可显著降低 eIF4B（真核起始因子 4B）的水平，并因此降低整体蛋白质翻译。通过生化研究，我们确定 eIF4B 是 USP11 的真正底物，USP11 稳定并增强了 eIF4B 的活性。通过药理学和遗传方法，我们确定 FASN 诱导的 PI3K-S6K 信号通路磷酸化 USP11，增强其与 eIF4B 的相互作用，从而促进致癌翻译。
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