The acetyl-CoA carboxylase enzyme: a target for cancer therapy?

Wang, Chao; Ma, Jun; Zhang, Nan; Yang, Qin; Jin, Yue; Wang, Yu

doi:10.1586/14737140.2015.1038246

Cited by 75 publications

(69 citation statements)

References 92 publications

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“…25 Similarly, knockdown of ACAC, FASN, and SCD1 by siRNA or inhibition of ACC or FASN with small molecular inhibitors were found to impair tumor cell proliferation and induces apoptosis in various in vitro and in vivo cancer models. 22,26,27 Altogether, this body of information supports a pivotal role of lipogenic proteins and de novo lipid synthesis in cancer initiation and progression.…”

Section: De Novo Lipogenesis In Cancermentioning

confidence: 70%

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

et al. 2017

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Hepatocellular carcinoma (HCC), the most frequent primary tumor of the liver, is an aggressive cancer type with limited treatment options. Cumulating evidence underlines a crucial role of aberrant lipid biosynthesis (a process known as de novo lipogenesis) along carcinogenesis. Previous studies showed that suppression of fatty acid synthase (FASN), the major enzyme responsible for de novo lipogenesis, is highly detrimental for the in vitro growth of HCC cell lines. To assess whether de novo lipogenesis is required for liver carcinogenesis, we have generated various mouse models of liver cancer by stably overexpressing candidate oncogenes in the mouse liver via hydrodynamic gene delivery. We found that overexpression of FASN in the mouse liver is unable to malignantly transform hepatocytes. However, genetic deletion of FASN totally suppresses hepatocarcinogenesis driven by AKT and AKT/c-Met protooncogenes in mice. On the other hand, liver tumor development is completely unaffected by FASN depletion in mice coexpressing b-catenin and c-Met. Our data indicate that tumors might be either addicted to or independent from de novo lipogenesis for their growth depending on the oncogenes involved. Additional investigation is required to unravel the molecular mechanisms whereby some oncogenes render cancer cells resistant to inhibition of de novo lipogenesis.

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Section: De Novo Lipogenesis In Cancermentioning

confidence: 70%

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

et al. 2017

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“…Despite its promise as a target for anti-cancer therapeutics [1, 12, 50, 51], the mechanism by which FASN is dysregulated in cancer is unknown. Similarly, two enzymes catalyzing rate limiting steps upstream of FASN in de novo fatty acid synthesis, ACC and ACLY, are often dysregulated in cancer and have been proposed as breast cancer therapeutic targets [52–54]. …”

Section: Discussionmentioning

confidence: 99%

The BRG1 chromatin remodeling enzyme links cancer cell metabolism and proliferation

Madany

Dobson

et al. 2016

Oncotarget

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Cancer cells reprogram cellular metabolism to meet the demands of growth. Identification of the regulatory machinery that regulates cancer-specific metabolic changes may open new avenues for anti-cancer therapeutics. The epigenetic regulator BRG1 is a catalytic ATPase for some mammalian SWI/SNF chromatin remodeling enzymes. BRG1 is a well-characterized tumor suppressor in some human cancers, but is frequently overexpressed without mutation in other cancers, including breast cancer. Here we demonstrate that BRG1 upregulates de novo lipogenesis and that this is crucial for cancer cell proliferation. Knockdown of BRG1 attenuates lipid synthesis by impairing the transcription of enzymes catalyzing fatty acid and lipid synthesis. Remarkably, exogenous addition of palmitate, the key intermediate in fatty acid synthesis, rescued the cancer cell proliferation defect caused by BRG1 knockdown. Our work suggests that targeting BRG1 to reduce lipid metabolism and, thereby, to reduce proliferation, has promise for epigenetic therapy in triple negative breast cancer.

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“…The synthesis of malonyl-CoA from precursor molecules acetyl-CoA and CO 2 is the first committed step of fatty acid synthesis (Cronan and Waldrop, 2002;Broussard et al, 2013). The enzyme responsible for this key reaction is Acetyl-CoA carboxylase (ACC), which is an essential enzyme strictly conserved in all organisms, from bacteria to humans (Cronan and Waldrop, 2002;Broussard et al, 2013;Wang et al, 2015). In bacteria, ACC is composed of four subunits, which assemble into three functional units; a homodimeric biotin carboxylase (BC), a biotinylated biotin carboxyl carrier protein (BCCP) and an a2b2 heterotetrameric carboxyltransferase (CT) (Cronan and Waldrop, 2002).…”

Section: Introductionmentioning

confidence: 99%

A revised model for the control of fatty acid synthesis by master regulator Spo0A in Bacillus subtilis

Haggett

Bhasin

Srivastava

et al. 2018

Molecular Microbiology

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In starving Bacillus subtilis cells, the accDA operon encoding two subunits of the essential acetyl-CoA carboxylase (ACC) has been proposed to be tightly regulated by direct binding of the master regulator Spo0A to a cis element (0A box) in the promoter region. When the 0A box is mutated, biofilm formation and sporulation have been reported to be impaired. Here, we present evidence that two 0A boxes, one previously known (0A-1) and another newly discovered (0A-2) in the accDA promoter region are positively and negatively regulated by Spo0A∼P respectively. Cells with mutated 0A boxes experience slight delays in sporulation, but eventually sporulate with high efficiency. In contrast, cells harboring a single mutated 0A-2 box are deficient for biofilm formation, while cells harboring either a mutated 0A-1 box or both mutated 0A boxes form biofilms. We further show that the essential ACC enzyme localizes on or near the cell membrane by directly observing a functional GFP fusion to one of the enzyme's subunits. Collectively, we propose a revised model in which accDA is primarily transcribed by a major σ -RNA polymerase, while Spo0A∼P plays an additional role in the fine-tuning of accDA expression upon starvation to support proper biofilm formation and sporulation.

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The acetyl-CoA carboxylase enzyme: a target for cancer therapy?

Cited by 75 publications

References 92 publications

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

The BRG1 chromatin remodeling enzyme links cancer cell metabolism and proliferation

A revised model for the control of fatty acid synthesis by master regulator Spo0A in Bacillus subtilis

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