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Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth

Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth

Jun Fan, Ruiting Lin, Siyuan Xia, Dong Chen, Shannon E Elf, Shuangping Liu, Yaozhu Pan, Haidong Xu, Zhiyu Qian, Mei Wang, Changliang Shan, Lu Zhou, Qun-Ying Lei, Yuancheng Li, Hui Mao, Benjamin H Lee, Jessica Sudderth, etc.

Mol Cell. 2016 Dec 1;64(5):859-874.

PMID: 27867011

Abstract:

Mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) regulates pyruvate dehydrogenase complex (PDC) by acetylating pyruvate dehydrogenase (PDH) and PDH phosphatase. How ACAT1 is "hijacked" to contribute to the Warburg effect in human cancer remains unclear. We found that active, tetrameric ACAT1 is commonly upregulated in cells stimulated by EGF and in diverse human cancer cells, where ACAT1 tetramers, but not monomers, are phosphorylated and stabilized by enhanced Y407 phosphorylation. Moreover, we identified arecoline hydrobromide (AH) as a covalent ACAT1 inhibitor that binds to and disrupts only ACAT1 tetramers. The resultant AH-bound ACAT1 monomers cannot reform tetramers. Inhibition of tetrameric ACAT1 by abolishing Y407 phosphorylation or AH treatment results in decreased ACAT1 activity, leading to increased PDC flux and oxidative phosphorylation with attenuated cancer cell proliferation and tumor growth. These findings provide a mechanistic understanding of how oncogenic events signal through distinct acetyltransferases to regulate cancer metabolism and suggest ACAT1 as an anti-cancer target.

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AP115035466	Gly-Pro-7-amido-4-methylcoumarin hydrobromide	115035-46-6	Price
IAR4245002	SKF-89145 hydrobromide		Price

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