High mobility group A1 (HMGA1) promotes the tumorigenesis of colorectal cancer by increasing lipid synthesis

Yuan Zhao, Meng-Jie Liu, Lei Zhang, Qi Yang, Qian-Hui Sun, Jin-Rong Guo, Xin-Yuan Lei, Kai-Yue He, Jun-Qi Li, Jing-Yu Yang, Yong-Ping Jian () and Zhi-Xiang Xu ()
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Yuan Zhao: Henan University
Meng-Jie Liu: Henan University
Lei Zhang: Henan University
Qi Yang: Henan University
Qian-Hui Sun: Henan University
Jin-Rong Guo: Henan University
Xin-Yuan Lei: Henan University
Kai-Yue He: Henan University
Jun-Qi Li: Henan University
Jing-Yu Yang: Henan University
Yong-Ping Jian: Henan University
Zhi-Xiang Xu: Henan University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54400-0

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