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CDCA4 promotes lipid metabolism in triple-negative breast cancer through activation of the SESN2/mTOR/SREBP1 pathway

ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by high metastatic potential, poor prognosis, and limited therapeutic options. However, the molecular mechanisms underlying TNBC progression and metabolic reprogramming remain incompletely understood. In this study, we identified cell division cycle-associated 4 (CDCA4) as a potential oncogenic driver in TNBC. Analysis of the TCGA-BRCA dataset revealed that CDCA4 was significantly upregulated in breast cancer tissues compared with normal tissues and was expressed at higher levels in TNBC than in non-TNBC. Elevated CDCA4 expression was also associated with poor overall survival in TNBC patients. Functional experiments demonstrated that CDCA4 knockdown suppressed TNBC cell proliferation, migration, invasion, and xenograft tumor growth, whereas CDCA4 overexpression exerted the opposite effects. RNA-sequencing analysis indicated that CDCA4-regulated genes were significantly enriched in lipid metabolism-related pathways and metabolism-associated signaling pathways, including PI3K/AKT and mTOR. Consistently, CDCA4 depletion reduced intracellular free fatty acids, total cholesterol, triglycerides, lipid accumulation, and the expression of lipogenic enzymes, including FASN and ACC1. Mechanistically, CDCA4 promoted mTOR activation and increased the level of the active nuclear form of SREBP1, thereby enhancing SREBP1 occupancy at the FASN and ACC1 promoter regions. Pharmacological inhibition of mTOR largely reversed CDCA4-induced malignant phenotypes and lipid metabolic alterations. Furthermore, we identified SESN2 as a critical mediator linking CDCA4 to mTOR activation, as SESN2 knockdown attenuated mTOR signaling and reversed the protumorigenic effects induced by CDCA4 overexpression. Collectively, these findings demonstrate that CDCA4 drives TNBC progression and lipid metabolic reprogramming through the SESN2/mTOR/SREBP1 axis, highlighting CDCA4 as a potential prognostic biomarker and therapeutic target in TNBC.

ORGANISM(S): Mus musculus

PROVIDER: GSE330488 | GEO | 2026/08/19

REPOSITORIES: GEO

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Project description:Metabolic reprogramming is a typical feature of tumors, in which biological macromolecules and energy produced in abnormal metabolism meet the requirements of highly proliferative tumor cells and participate in multiple stages of tumor development. High mobility group A1 (HMGA1) is a structural transcription factor, which plays a carcinogenic role in regulating the transcription of oncogenes. Bioinformatics analysis showed that HMGA1 was overexpressed in human CRC. However, the mechanisms by which HMGA1 promotes the tumorigenesis of CRC remains unknown. Herein, we applied intestinal epithelium conditional knockout (Hmga1△IEC) and knock-in (Hmga1IEC-OE/+) mice of HMGA1 to induce CRC, and identified that HMGA1 promotes colorectal cancer growth by increasing lipid synthesis. Single-cell sequencing (scRNA seq) and immunohistochemical staining showed that HMGA1 was highly expressed in the epithelial cells of CRC. HMGA1 promoted the CRC cell proliferation and accelerated CRC development in HMGA1-knock-in (Hmga1IEC-OE/+) mice. Knockout of HMGA1 (Hmga1△IEC) in intestinal epithelial cells of mice reduced the lipid accumulation and inhibited the occurrence and development of CRC. We further characterized that HMGA1 upregulated the level of fatty acid synthase (FASN) through enhancing the transcriptional binding of sterol regulatory element-binding protein 1 (SREBP1) to the promoter of FASN, leading to an increase in lipid synthesis in intestinal epithelial cells. High fat diet (HFD) aggravated the malignant progression of CRC in Hmga1△IEC mice and reversed the inhibitory effect of HMGA1 depletion on CRC. Administration Orlistat (50 mg/kg), an inhibitor of FASN-mediated lipid synthesis, into Hmga1-knock-in (Hmga1IEC-OE/+) mice markedly reduced lipid accumulation in intestinal epithelial cells and decreased the tumorigenesis of CRC. Taken together, our data suggest that HMGA1 promotes the tumorigenesis of colorectal cancer by up-regulating FASN-mediated de novo fatty acid synthesis. Our findings provide strong evidence supporting therapeutic intervention of lipid accumulation for the prevention and treatment of CRC

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CDCA4 promotes lipid metabolism in triple-negative breast cancer through activation of the SESN2/mTOR/SREBP1 pathway

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