What is the mechanism for the BRG1 requirement for breast cancer cell proliferation? We discovered that BRG1 promotes breast cancer by reprogramming lipid synthesis (28) as shown in Figure 1. BRG1 knockdown reduced the rate of chloroform/methanol extractable lipid synthesis by 35% while glucose uptake remained unchanged. mRNA and protein levels for ACC, ACLY, and FASN, the key enzymes in de novo fatty acid synthesis, were all significantly decreased in BRG1 knockdown cells as were other important proteins performing or regulating lipid synthesis such as Lipin1. BRG1 bound to the promoters of all of these genes, and the promoter binding was diminished in BRG1 knockdown cells, evidence of direct BRG1 transcriptional control. Treatment with either an ACC inhibitor or a FASN inhibitor decreased cell number, and BRG1 knockdown cells showed increased sensitivity to these inhibitors. Remarkably, addition of exogenous palmitate, the key intermediate in fatty acid synthesis, completely rescued proliferation. Our work supports a mechanism in which BRG1 transcriptionally promotes de novo lipid synthesis, which is necessary for maintaining high rates of proliferation. In these cells, exogenous palmitate can substitute
