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

Abstract

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.

NFYA promotes the anti-tumor effects of gluconeogenesis in hepatocellular carcinoma through the regulation of PCK1 expression

“…To investigate the anti-tumor effects of gluconeogenesis regulation by NFYA on HCC, we examined the expression of NFYA and gluconeogenic enzymes in five different HCC cell lines. The expression of NFYA variants was associated with epithelial-mesenchymal transition (EMT) status as reported in breast cancer cells ( Dolfini et al, 2019 ; Okada et al, 2022 ), but no association was observed for the expression of PCK1 and G6PC ( Figure 2A ). PCK1 and G6PC were highly expressed in HepG2 cells, moderately expressed in Hep3B, Huh4, and Huh-7 cells, and barely expressed in SK-Hep1 cells ( Figure 2A ).…”

“…CUT&RUN experiments were performed as previously described ( Okada et al, 2022 ) with the CUT&RUN assay kit (CST, 86652). In brief, cells were collected 5 h after glucose deprivation treatment, washed, bound to activated Concanavalin A magnetic beads, and permeabilized with antibody binding buffer containing Digitonin.…”

“…Finally, we examined the correlation between NFYA and PCK1 in human hepatocellular carcinomas. It has been reported that the expression of splicing variants of NFYA strongly correlates with the expression of EMT markers, CDH1 and VIM (Figure 2A; Dolfini et al, 2019;Okada et al, 2022). Therefore, to investigate the correlation between each NFYA variant and PCK1 in 297 liver cancers using RNA-seq data from TCGA, we classified by the logFC of VIM/CDH1 into two groups: those predominantly expressing NFYAv1 (1 < logFC) and those predominantly expressing NFYAv2 (logFC < −1).…”

“…NFYA has a DNA-binding domain at the C-terminus and is thought to function as a limiting subunit of the NF-Y complex because point mutations in the DNA-binding domain inhibit NF-Y-DNA complex formation ( Mantovanis et al, 1994 ). NFYA has two types of splicing variants: a long-form (NFYAv1) and a short-form (NFYAv2) that lacks the 29 amino acids encoded by exon 3, including the Q-rich transactivation domain, and these two variants have been reported to perform different functions in breast cancer ( Li et al, 1992 ; Okada et al, 2022 ). In breast cancer, it has been reported that NFYAv1 regulates lipid metabolism and promotes tumor malignant behavior, while NFYAv2 has no effects.…”

NFYA promotes the anti-tumor effects of gluconeogenesis in hepatocellular carcinoma through the regulation of PCK1 expression

“…CUT&RUN experiments were performed as previously described (Okada et al, 2022) with the CUT&RUN assay kit (CST, 86652). In brief, cells were collected 5 hours after glucose deprivation treatment, washed, bound to activated Concanavalin A magnetic beads, and permeabilized with antibody binding buffer containing Digitonin.…”