SREBP2 as a central player in cancer progression: potential for targeted therapeutics

Ruiqi Chen ¹ Tianyu Chen ¹ Xiang Li ¹ Junfeng Yu ¹ Min Lin ² Siqi Wen ² Man Zhang ² Jinchi Chen ² Bei Yi ² Huage Zhong ^1,3* Zhao Li ^2*

• ¹ Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi Zhuang Region, China
• ² Department of Experimental Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Region, China
• ³ Guangxi Clinical Research Center for Colorectal Cancer, Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi Zhuang Region, China

Recent studies have identified the reprogramming of lipid metabolism as a critical hallmark of malignancy. Enhanced cholesterol uptake and increased cholesterol biosynthesis significantly contribute to the rapid growth of tumors, with cholesterol also playing essential roles in cellular signaling pathways. Targeting cholesterol metabolism has emerged as a promising therapeutic strategy in oncology. The sterol regulatory element-binding protein-2 (SREBP2) serves as a primary transcriptional regulator of genes involved in cholesterol biosynthesis and is crucial for maintaining cholesterol homeostasis. Numerous studies have reported the upregulation of SREBP2 across various cancers, facilitating tumor progression. This review aims to provide a comprehensive overview of the structure, biological functions, and regulatory mechanisms of SREBP2. Furthermore, we summarize that SREBP2 plays a crucial role in various cancers and tumor microenvironment primarily by regulating cholesterol, as well as through several non-cholesterol pathways. We also particularly emphasize therapeutic agents targeting SREBP2 that are currently under investigation. This review seeks to enhance our understanding of SREBP2's involvement in cancer and provide theoretical references for cancer therapies that target SREBP2.