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 cleavage-activating 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.

Wnt signaling mediates oncogenic synergy between Akt and Dlx5 in T-cell lymphomagenesis by enhancing cholesterol synthesis

“…Oncogenesis is sustained by cancer anabolism, of which lipid biosynthesis plays an important role. Rewired lipid metabolism is now considered a hallmark of cancer, and enhanced lipid uptake and lipogenesis are well documented in many cancers and facilitate tumorigenesis 27 . Cholesterol-reducing statins have been reported to suppress tumor cell proliferation 28 .…”

SCAP Mediated GDF15-Induced Invasion and EMT of Esophageal Cancer

“…However, the role of GDF15 in the invasion and metastasis of EC remains poorly understood. Both TGFβ1 and GDF15 belongs to TGF-β superfamily, TGFβ1 was reported to activate SREBP2 in kidney mesangial cells, SREBF2 activation was dependent on SCAP ( 11 , 12 ), SCAP or SREBPs promoted tumor progression in various cancer ( 13 ). Therefore, we speculated that GDF15 may also regulate the invasion and metastasis of EC through SCAP/SREBF2 axis, which involved cholesterol synthesis and uptake.…”

“…TGFβ1 has been reported to activate the sterol regulatory element-binding protein 2 (SREBP2) in kidney mesangial cells, and SREBF2 activation was dependent on sterol regulatory element-binding protein cleavage-activating protein (SCAP) ( 11 , 12 ), inhibition of SCAP or SREBPs significantly suppressed tumor growth in various cancer ( 13 ). As a divergent member of the TGF-β superfamily, GDF15 may also promote the progression of EC through SCAP/SREBPs pathway.…”

Lipid Metabolism Alteration by Endocrine Disruptors in Animal Models: An Overview

“…In addition to PPARɤ, several genes regulate fat cell development and control, including CCAAT-enhancer-binding proteins ( c/ebp ), responsible for the secretion of adipokines, e.g., leptin and adiponectin, hepatic glucose metabolism, insulin sensitivity and inflammation ( 24 ). A side from PPARs and C/EBP, sterol regulatory element-binding proteins (SREBPs) are central players in lipid metabolism, controlling the expression of genes important for lipid synthesis and uptake ( 25 ). In addition to the canonical functions in the transcriptional regulation of genes involved in lipid biosynthesis and uptake, SREBPs are also implicated in pathogenic processes including, inflammation, autophagy and apoptosis, and in this way, they contribute to the onset of several metabolic disorders ( 26 ).…”

“…Among phthalates, the di-ethyl-hexyl-phthalate (DEHP) exerts its obesogenic action up-regulating hepatic ppar α , cb1 , and srebp levels and stimulating de novo FA synthesis and hepatic steatosis. This hepatic state may cause an inhibition of food intake stimulus up-regulating leptin, the typical sensor of the energy status, which, in the brain, may negatively control cb1 and in turn reduce srebp gene expression ( 25 ).…”