1. High mobility group A1 (HMGA1) promotes the tumorigenesis of colorectal cancer by increasing lipid synthesis.
- Author
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Zhao, Yuan, Liu, Meng-Jie, Zhang, Lei, Yang, Qi, Sun, Qian-Hui, Guo, Jin-Rong, Lei, Xin-Yuan, He, Kai-Yue, Li, Jun-Qi, Yang, Jing-Yu, Jian, Yong-Ping, and Xu, Zhi-Xiang
- Abstract
Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to meet the high energy and biosynthetic demands required for their proliferation. High mobility group A1 (HMGA1) is a structural transcription factor and frequently overexpressed in human colorectal cancer (CRC). Here, we show that HMGA1 promotes CRC progression by driving lipid synthesis in a AOM/DSS-induced CRC mouse model. Using conditional knockout (Hmga1
△IEC ) and knock-in (Hmga1IEC-OE/+ ) mouse models, we demonstrate that HMGA1 enhances CRC cell proliferation and accelerates tumor development by upregulating fatty acid synthase (FASN). Mechanistically, HMGA1 increases the transcriptional activity of sterol regulatory element-binding protein 1 (SREBP1) on the FASN promoter, leading to increased lipid accumulation in intestinal epithelial cells. Moreover, a high-fat diet exacerbates CRC progression in Hmga1△IEC mice, while pharmacological inhibition of FASN by orlistat reduces tumor growth in Hmga1IEC-OE/+ mice. Our findings suggest that targeting lipid metabolism could offer a promising therapeutic strategy for CRC. Metabolic reprogramming is crucial for cancer progression. Here, the authors show that the high mobility group A1 (HMGA1) promotes colorectal cancer (CRC) in a AOM/DSS-induced mouse model, by enhancing lipid synthesis via upregulation of fatty acid synthase (FASN), and inhibiting FASN reduces tumor growth, suggesting potential therapeutic avenues. [ABSTRACT FROM AUTHOR]- Published
- 2024
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