Targeting SREBP-1-Mediated Lipogenesis as Potential Strategies for Cancer

Abstract

Sterol regulatory element binding protein-1 (SREBP-1), a transcription factor with a basic helix-loop-helix leucine zipper, has two isoforms, SREBP-1a and SREBP-1c, derived from the same gene for regulating the genes of lipogenesis, including acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase. Importantly, SREBP-1 participates in metabolic reprogramming of various cancers and has been a biomarker for the prognosis or drug efficacy for the patients with cancer. In this review, we first introduced the structure, activation, and key upstream signaling pathway of SREBP-1. Then, the potential targets and molecular mechanisms of SREBP-1-regulated lipogenesis in various types of cancer, such as colorectal, prostate, breast, and hepatocellular cancer, were summarized. We also discussed potential therapies targeting the SREBP-1-regulated pathway by small molecules, natural products, or the extracts of herbs against tumor progression. This review could provide new insights in understanding advanced findings about SREBP-1-mediated lipogenesis in cancer and its potential as a target for cancer therapeutics.

Keywords: SREBP-1; cancer therapy; fatty acid synthase; fatty acids; lipogenesis.

Figure 1

SREBP-1 structure, activation, and signaling pathways. (A) SREBP-1 structure and activation. SREBP-1 contains the NH2-terminal domain (the bHLH-Zip motif and an acidic motif), a middle hydrophilic region, and the COOH-terminal domain. (B) After INSIG dissociation from SCAP, SREBP-1 translocates to the Golgi apparatus and is cleaved by site 1 protease (S1P) and site 2 protease (S2P) to form a nuclear form (nSREBP-1) for activating the transcription of its downstream targets, such as FASN, ACC, SCD-1/5, ACLY, and LDLR. (C) Multiple signaling pathways regulate SREBP-1 expression, translocation, and maturation, including EGFR, PI3K/Akt/mTORC1, and others. OGT: O-GlcNAc transferase, GS: glutamate synthetase, TDG: thymine DNA glycosylase.

Figure 2

SREBP-1-mediated lipogenesis in the five types of cancers. Multiple pathways can regulate SREBP-1 and its downstream targets to mediate aggressive characteristics, including proliferation, invasion, migration, EMT, tumorigenesis, metastasis, angiogenesis, and drug resistance in colorectal, prostate, breast, hepatocellular cancer, and glioblastoma. Meanwhile, in these cancers, SREBP-1 activation can increase de novo lipogenesis and regulate fatty acid metabolic programming, lipid droplets, and sapienate metabolism. EMT: epithelial–mesenchymal transition, ER: endoplasmic reticulum, TGs: triglycerides.

Figure 3

The interaction of the treatment by small molecules, natural products, or the extract of herbs, the targets (SREBP-1 expression/cleavage/stability), effects, and cancer types. The pink/purple circles represent upstream and downstream targets of SREBP-1. The blue diamonds represent the effects from the inhibition of the SREBP-1 pathway. The orange rectangles represent cancer types. The number of edges connected between the nodes in the network represents the count of their connections.