SCAP/SREBPs are Central Players in Lipid Metabolism and Novel Metabolic Targets in Cancer Therapy

Abstract

Lipid metabolism reprogramming emerges as a new hallmark of malignancies. Sterol regulatory element-binding proteins (SREBPs), which are central players in lipid metabolism, are endoplasmic reticulum (ER)-bound transcription factors that control the expression of genes important for lipid synthesis and uptake. Their transcriptional activation requires binding to SREBP cleavageactivating protein (SCAP) to translocate their inactive precursors from the ER to the Golgi to undergo cleavage and subsequent nucleus translocation of their NH2-terminal forms. Recent studies have revealed that SREBPs are markedly upregulated in human cancers, providing the mechanistic link between lipid metabolism alterations and malignancies. Pharmacological or genetic inhibition of SCAP or SREBPs significantly suppresses tumor growth in various cancer models, demonstrating that SCAP/SREBPs could serve as promising metabolic targets for cancer therapy. In this review, we will summarize recent progress in our understanding of the underlying molecular mechanisms regulating SCAP/SREBPs and lipid metabolism in malignancies, discuss new findings about SREBP trafficking, which requires SCAP N-glycosylation, and introduce a newly identified microRNA-29-mediated negative feedback regulation of the SCAP/SREBP pathway. Moreover, we will review recently developed inhibitors targeting the SCAP/SREBP pathway for cancer treatment.

Keywords: EGFR; Lipid metabolism; Metabolic targets; SCAP; SREBPs; miRNA-29..

Figure 1.

Regulation of SCAP/SREBP activation in Cancer Cells. In cancer cells, oncogenic EGFR signaling increases glucose uptake and enhances the synthesis of UDPGlcNAc, the end-product of the hexosamine synthesis pathway, promoting the N-glycosylation of SCAP, which enables SCAP dissociation from INSIG and leads to SCAP/SREBP trafficking from the ER to the Golgi. In the Golgi, SREBPs are sequentially cleaved by S1P and S2P proteases to release their NH2-terminal forms, which enter into the nucleus to activate the expression of key lipogenic genes, including themselves, forming a feedforward loop to activate lipid metabolism. Moreover, the newly synthesized INSIG1, cholesterol and unsaturated fatty acids mediated by SREBPs enhance the binding of INSIG and SCAP to retain SCAP/SREBP complex in the ER, forming a negative feedback loop to regulate SREBP activation. In addition, the nuclear SREBP forms are degraded by ubiquitin E3 ligase FBXW-mediated proteasome system, a process regulated by phosphorylation, acetylation and sumoylation by GSK3β, SIRT1 and PIAsy, respectively. Recently, miR-29 was found to be transcriptionally upregulated by SREBP-1, and in turn to inhibit SCAP and SREBP expression, mediating an additional negative feedback loop controlling this signaling pathway. Various inhibitors shown in blue, which inhibit SREBP translocation or maturation, have been tested in cancer cells and have shown promising anti-tumor effects. Abbreviation: ACACA, acetyl-coA carboxylase alpha; ACACB, acetyl-coA carboxylase beta; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; FAs, fatty acids; FASN, fatty acid synthase; FBXW, F-box and WD repeat domain containing; GSK3β, glycogen synthase kinase-3 beta; HMGCR, hydroxymethylglutaryl-CoA reductase; INSIG, insulin-induced gene proteins; LDLR, low density lipoprotein receptor; PIASy, STAT Y; S1P, site-1 protease; S2P, site-2 protease; SCAP, SREBP cleavage-activating protein; SIRT1, sirtuin 1; SREBP, Sterol regulatory element-binding proteins; nSREBPs, nuclear forms of SREBPs.

Figure 2.

The structure of inhibitors in SCAP/SREBPs pathway. A) Inhibitors suppressing SCAP/SREBP trafficking; B) Inhibitor suppressing S1P or S2P; C) Inhibitors suppressing the transcriptional activity of SREBPs.