Zinc Finger SWIM-Type Containing 3 Reprograms Lipid Metabolism and Drives Breast Cancer Progression.

Abstract

Background: Zinc finger proteins (ZNFs) have been proved to play important roles in driving the progression of breast cancer (BC), one of the most common cancers among women. This study aimed to investigate the involvement of zinc-finger SWIM domain-containing protein 3 (ZSWIM3) in promoting BC cell progression by regulating lipid metabolism.

Methods: Differential expression of ZSWIM3 in BC was confirmed by comparing its expression in normal human mammary epithelial cells and BC cells. MCF7 cells, a BC cell line, were subjected to ZSWIM3 knockdown/overexpression experiments. The lipid contents in MCF7 cells were measured by assay kits and immunofluorescence test. The lipogenic enzymes in the cells were detected by enzyme-linked immunosorbent assay (ELISA). The cells were also subjected to further transfection experiments to manipulate the expression of sterol regulatory element-binding transcription factor 1 (SREBF1)/SREBF2 in ZSWIM3-regulated MCF7 cells to verify whether the ZSWIM3 targets SREBF1/SREBF2. Subsequently, the lipid contents in the transfected cells were determined, and the cell viability, proliferation and metastasis were measured.

Results: ZSWIM3 was overexpressed in BC cells. ZSWIM3 knockdown/overexpression led to a significant decrease/increase of the lipid contents including triglyceride, free fatty acid, cholesterol, phospholipid and neutral lipid, and lipogenic enzymes (p < 0.01). The ZSWIM3 knockdown decreased the expression of SREBF1 and SREBF2 (p < 0.01). Our findings showed that lipid content reduction induced by ZSWIM3 knockdown was reversed by SREBF1/SREBF2 overexpression. MCF7 cell viability, proliferation and metastasis, which were all suppressed by ZSWIM3 knockdown (p < 0.001), were reversible through SREBF1/SREBF2 overexpression (p < 0.001). On the other hand, the ZSWIM3 overexpression increased SREBF1 and SREBF2 expression (p < 0.001). Lipid content elevation, as well as increased MCF7 cell viability, proliferation and metastasis, which were induced by ZSWIM3 overexpression, could be counteracted by SREBF1/SREBF2 downregulation (p < 0.001).

Conclusion: ZSWIM3 promotes BC progression by enhancing lipid synthesis. This study reveals the malevolent effect of ZSWIM3 on BC, underpinned by the reprogramming of lipid metabolism, providing insights into potential therapeutic targets for BC treatments.