Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

Abstract

Recently, targeting metabolic reprogramming has emerged as a potential therapeutic approach for fighting cancer. Sterol regulatory element binding protein-2 (SREBP-2), a basic helix-loop-helix leucine zipper transcription factor, mainly regulates genes involved in cholesterol biosynthesis and homeostasis. SREBP-2 binds to the sterol regulatory elements (SREs) in the promoters of its target genes and activates the transcription of mevalonate pathway genes, such as HMG-CoA reductase (HMGCR), mevalonate kinase and other key enzymes. In this review, we first summarized the structure of SREBP-2 and its activation and regulation by multiple signaling pathways. We then found that SREBP-2 and its regulated enzymes, including HMGCR, FPPS, SQS, and DHCR4 from the mevalonate pathway, participate in the progression of various cancers, including prostate, breast, lung, and hepatocellular cancer, as potential targets. Importantly, preclinical and clinical research demonstrated that fatostatin, statins, and N-BPs targeting SREBP-2, HMGCR, and FPPS, respectively, alone or in combination with other drugs, have been used for the treatment of different cancers. This review summarizes new insights into the critical role of the SREBP-2-regulated mevalonate pathway for cancer and its potential for targeted cancer therapy.

Keywords: HMG-CoA reductase; SREBP-2; cancer therapy; cholesterol; mevalonate.

Figure 1

SREBP-2 structure, activation, and regulation. (A) SREBP-2 protein consists of three domains, including an NH2-terminal regulatory domain, a middle hydrophilic region, and a COOH-terminal regulatory domain. The NH2-terminal domain contains the bHLH-Zip motif and an acidic transcriptional motif. (B) SREBP-2 activation, transport, and translocation. After INSIG dissociation from SCAP by sterol depletion, SREBP-2 translocates to the Golgi apparatus and is cleaved by S1P and S2P proteases to release the NH2-terminal fragment of SREBP-2 (nSREBP-2). nSREBP-2 translocation and stability are regulated by multiple signaling pathways at different levels. ER, endoplasmic reticulum; INSIG, insulin-induced gene protein; SCAP, SREBP cleavage-activation protein; COPII, coatomer protein II; S1P, site-1 protease; S2P, site-2 protease; Ub, ubiquitination; GSK3, glycogen synthase kinase 3; P, phosphorylation; SCF-Fbw7, SKP1-cullin-F-Box protein-F-box and WD repeat domain-containing 7; AMPK, adenosine monophosphate-activated protein kinase; MAPK, mitogen-activated protein kinase; p300/CBP, p300 and cyclic AMP response element-binding protein; Ac, acetylation; S, Sumoylation; SRE, sterol regulatory element; GP78, a membrane-anchored ubiquitin ligase; PAQR3, progestin and adipoQ receptors member 3; ERBB4, Erb-b2 receptor tyrosine kinase 4; GD3, a dominant melanoma ganglioside; HSP90, heat shock protein 90; TRC8, translocation in renal cancer from chromosome 8; RNF145, RNF finger protein 145.

Figure 2

The SREBP-regulated mevalonate pathway and its regulation. Schematic representation summarizing the SREBP-2-regulated mevalonate pathway and key enzymes for synthesis from acetyl-CoA to cholesterol and its products. Multiple signaling pathways such as p53, Akt, and androgen can regulate SREBP-2 activation. Several regulatory feedback mechanisms exist for different enzymes by various signals and mevalonate metabolites, such as cholesterol, IPP (Isopentenylpyrophosphate) and FPP (farnesylpyrophosphate). ACAT, acyl CoA-cholesterol acyltransferase; HMGCSm HMG-CoA synthase; HMGCR, HMG-CoA reductase; MVK, mevalonate kinase; MVD, HMG-CoA synthase; PMVK, phosphomevalonate kinase; IDI, isopentenyl diphosphate isomerase; FPPS, farnesylpyrophosphate synthase; SQS, squalene synthase; SQLE, squalene epoxidase; LSS, lanosterol synthase; CYP51A, lanosterol-14α demethylase; TM7SF2, steroid 14 reductase; SC4MOL, 4 methyl sterol oxidase; NSDHL, C3 sterol dehydrogenase; HSD17B7, 3-ketoreductase, EBP, phenylalkylamine Ca²⁺ antagonist binding protein; SC5D, sterol-C5-desaturase; DHCR7, 7-dehydrocholesterol reductase; DHCR24, 24-dihydrocholesterol reductase; LDLR, low-density lipoprotein receptors; GGPP, geranylgeranylpyrophosphate; AMPK, adenosine monophosphate-activated protein kinase; PPARγ, peroxisome proliferators-activated receptor γ; INSIG, insulin-induced gene protein; LXR, Liver X receptor; REST, RE1-silencing transcription factor.