NFYA promotes the malignant behavior of triple-negative breast cancer through the regulation of lipid metabolism

Two splicing variants exist in NFYA, which exhibits high expression in many human tumor types, and their expression balance is known to correlate with prognosis in breast cancer, but functional differences are still unclear. Here, we demonstrate that NFYAv1, the long-form variant, upregulates the transcription of ACACA and FASN, essential lipogenic enzymes, to enhance the malignant behavior of triple-negative breast cancer (TNBC). Loss of the NFYAv1-lipogenesis axis strongly suppresses the malignant behavior in vitro and in vivo, indicating that the NFYAv1-lipogenesis axis is essential for TNBC malignant behavior and that the axis might be a potential therapeutic target for TNBC. Furthermore, mice deficient in lipogenic enzymes such as Acly, Acaca, and Fasn exhibit embryonic lethality, but our Nfyav1-deficient mice have no apparent developmental abnormalities. Taken together, our results elucidate NFYAv1-lipogenesis axis has significant tumor-promoting effects and the potential for NFYAv1 to be a safer therapeutic target for TNBC.