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

Abstract

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.

Keywords: SREBP2; cancer; cancer therapy; cholesterol metabolism; tumor microenvironment.

FIGURE 1

Structure of SREBP2. (Created in BioRender. Chen, R. (2025) https://BioRender.com/r73a111). The SREBP2 protein comprises three main segments: an NH2-terminal domain of approximately 480 amino acids, a middle hydrophobic region of approximately 80 amino acids, and a COOH-terminal domain of approximately 590 amino acids. The NH2-terminal domain contains an acidic region that is responsible for transcriptional activation, as well as a basic helix-loop-helix-leucine zipper (bHLH-Zip) motif that specifically binds to DNA sequences.

FIGURE 2

Transcription regulation of SREBP2. (Created in BioRender. Chen, R. (2024) https://BioRender.com/h24n110). The transcription start site of SREBP2 contains binding sites for the transcription factors SP1 and NF-Y, along with a 10-base pair SRE. SP1 and NF-Y cooperate with n-SREBP2 to upregulate the transcription of SREBP2. FOXO3 acts as a negative regulator by binding to a conserved insulin response element (IRE) in the SREBP2 gene and recruiting SIRT6. Subsequently, SIRT6 deacetylates histone H3 in the SREBP2 gene promoter, thereby suppressing SREBP2 expression.

FIGURE 3

Post-transcriptional regulation and post-translational modifications of SREBP2. (Created in BioRender. Chen, R. (2024) https://BioRender.com/q25n513). miR-185, miR-185-5p, miR-195, miR-130b, miR-328-3p, and miR-98 directly bind to the 3′-untranslated region (3′UTR) of SREBP2 mRNA, leading to the inhibition of its expression. MARCHF6 serves as a primary ubiquitin ligase that promotes SREBP2 degradation. XBP1-u and KIF11 inhibit the ubiquitination and proteasomal degradation of SREBP2.

FIGURE 4

Activation regulation of SREBP2. (Created in BioRender. Chen, R. (2025) https://BioRender.com/xugbutl). Under cholesterol depletion: The SCAP-SREBP2 complex binds to COPII vesicles, facilitating its translocation to the Golgi apparatus. PAQR3 interacts with the SCAP-SREBP2 complex in the Golgi, retaining it within this organelle. Sequential proteolytic cleavage by Site-1 protease (S1P) and Site-2 protease (S2P) generates nuclear SREBP2 (n-SREBP2), which translocates to the nucleus as a homodimer to bind sterol regulatory elements (SREs) and activate transcription of target genes. Under cholesterol repletion: SCAP binds to INSIG, forming an ER-anchored INSIG/SCAP/SREBP complex that inhibits the transport of SREBP2 to the Golgi apparatus.

FIGURE 5

Regulation of n-SREBP2 protein. (Created in BioRender. Chen, R. (2024) https://BioRender.com/z88u544). mTORC1 phosphorylates lipin 1, reducing its nuclear entry. Lipin 1 decreases n-SREBP2 levels. The histone acetyltransferase p300 and its related protein CBP acetylate n-SREBP2 to enhance its transcriptional activity, while Sirtuin1 (SIRT1) deacetylates n-SREBP2. Additionally, phosphorylation of n-SREBP2 by ERK proteins also increases its transcriptional activity. Conversely, AMP-activated protein kinase (AMPK) phosphorylates n-SREBP2, inhibiting its nuclear translocation and transcriptional activity. SUMO1-mediated SUMOylation of n-SREBP2 also suppresses its transcriptional activity. Serine/threonine protein kinase GSK3 phosphorylates n-SREBP2, mediating its proteasomal degradation via the SCF-FBW7 ubiquitin ligase complex, thereby reducing n-SREBP2 levels. Carbohydrate response element-binding protein (ChREBP) also promotes n-SREBP2 ubiquitination and proteasomal degradation.