Analysis of SCAP &lt;em&gt;N&lt;/em&gt;-glycosylation and Trafficking in Human Cells

Cheng, Chunming; Guo, Jeffrey Yunhua; Geng, Feng; Wu, Xiaoning; Cheng, Xiang; Li, Qiyue; Guo, Deliang

doi:10.3791/54709

Cited by 15 publications

(16 citation statements)

References 41 publications

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“…We found that GBM tumors bearing amplified EGFR, or expressing EGFRvIII, the constitutively active form of the receptor that lacks a portion of the extracellular ligand-binding domain, were greatly dependent on SREBP-1-mediated lipid synthesis and uptake for rapid growth [61]. EGFR/EGFRvIII activates SREBP-1 through upregulation of PI3K/Akt signaling, promoting the expression of ATP citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), stearoyl-coenzyme A desaturase 1 (SCD1) and low density lipoprotein receptor (LDLR) to enhance fatty acid synthesis and cholesterol uptake [13, 60, 61, 80, 83]. …”

Section: Activation Of Scap/srebps In Cancermentioning

confidence: 99%

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

Cheng

Guo

2018

CTMC

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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.

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Section: Activation Of Scap/srebps In Cancermentioning

confidence: 99%

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

Cheng

Guo

2018

CTMC

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“…To explore whether other factors are critical for SCAP/SREBP trafficking, we investigated the role of glucose-mediated N -glycosylation modification of the SCAP protein, and showed that it was a prerequisite step for SCAP/SREBP trafficking and activation upon cholesterol reduction [23–25] . We found that N -glycosylation stabilizes SCAP and reduces its association with Insig-1, allowing SCAP/SREBP movement from the ER to the Golgi (Fig.…”

mentioning

confidence: 99%

“…1). Our study demonstrated that glucose is an essential activator of SCAP/SREBP trafficking, while cholesterol functions as a key inhibitor of this process [23–25] .…”

mentioning

confidence: 99%

“…Our data show that GBM tumors bearing amplification of the tyrosine kinase receptor, EGFR, or expressing the constitutively active EGFRvIII, which lacks a portion of the extracellular ligand binding domain due to the deletion of exons 2–7 of the EGFR gene [39, 42, 43] , were greatly dependent on SREBP-1-mediated lipogenesis and cholesterol uptake for their rapid growth [34, 36, 44, 45] . We found that EGFR/EGFRvIII activates SREBP-1 via PI3K/Akt signaling to promote lipid synthesis [6, 10, 36] , and that EGFR signaling enhances glucose uptake to promote SCAP N -glycosylation and SCAP/SREBP-1 trafficking [23–25] .…”

mentioning

confidence: 99%

“…Our study was the first to show that miR-29 expression is controlled by SREBP-1, and that miR-29 is directly involved in the regulation of lipid metabolism. This newly discovered negative feedback loop regulation of SCAP/SREBP-1 by miR-29 further demonstrates that lipid homeostasis is elegantly regulated by multi-layer of mechanisms in addition to cholesterol and glucose regulation [23–25, 54] . Considering the simple synthesis and easy delivery of mature microRNAs, miR-29 treatment may be a feasible and promising approach to treat cancers and other metabolic diseases.…”

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confidence: 99%

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microRNA-29 mediates a novel negative feedback loop to regulate SCAP/SREBP-1 and lipid metabolism

Guo

2017

RNA Dis

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The membrane-bound transcription factors, SREBPs (sterol regulatory element-binding proteins), play a central role in regulating lipid metabolism. The transcriptional activation of SREBPs requires the key protein SCAP (SREBP-cleavage activating protein) to translocate their precursors from the endoplasmic reticulum to the Golgi for subsequent proteolytic activation, a process tightly regulated by a cholesterol-mediated negative feedback loop. Our previous work showed that the SCAP/SREBP-1 pathway is significantly upregulated in human glioblastoma (GBM), the most deadly brain cancer, and that glucose-mediated N-glycosylation of SCAP is a prerequisite step for SCAP/SREBP trafficking. More recently, we demonstrated that microRNA-29 (miR-29) mediates a previously unrecognized negative feedback loop in SCAP/SREBP-1 signaling to control lipid metabolism. We found that SREBP-1, functioning as a transcription factor, promotes the expression of the miR-29 family members, miR-29a, -29b and -29c. In turn, the miR-29 isoforms reversely repress the expression of SCAP and SREBP-1. Moreover, treatment with miR-29 mimics effectively suppressed GBM tumor growth by inhibiting SCAP/SREBP-1 and de novo lipid synthesis. These findings, recently published in Cell Reports, strongly suggest that delivery of miR-29 in vivo may be a promising approach to treat cancer and metabolic diseases by suppressing SCAP/SREBP-1-regulated lipid metabolism.

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Potential therapies targeting nuclear metabolic regulation in cancer

Chen,

Xu,

Liu

et al. 2023

MedComm

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The interplay between genetic alterations and metabolic dysregulation is increasingly recognized as a pivotal axis in cancer pathogenesis. Both elements are mutually reinforcing, thereby expediting the ontogeny and progression of malignant neoplasms. Intriguingly, recent findings have highlighted the translocation of metabolites and metabolic enzymes from the cytoplasm into the nuclear compartment, where they appear to be intimately associated with tumor cell proliferation. Despite these advancements, significant gaps persist in our understanding of their specific roles within the nuclear milieu, their modulatory effects on gene transcription and cellular proliferation, and the intricacies of their coordination with the genomic landscape. In this comprehensive review, we endeavor to elucidate the regulatory landscape of metabolic signaling within the nuclear domain, namely nuclear metabolic signaling involving metabolites and metabolic enzymes. We explore the roles and molecular mechanisms through which metabolic flux and enzymatic activity impact critical nuclear processes, including epigenetic modulation, DNA damage repair, and gene expression regulation. In conclusion, we underscore the paramount significance of nuclear metabolic signaling in cancer biology and enumerate potential therapeutic targets, associated pharmacological interventions, and implications for clinical applications. Importantly, these emergent findings not only augment our conceptual understanding of tumoral metabolism but also herald the potential for innovative therapeutic paradigms targeting the metabolism–genome transcriptional axis.

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Analysis of SCAP <em>N</em>-glycosylation and Trafficking in Human Cells

Cited by 15 publications

References 41 publications

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

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

microRNA-29 mediates a novel negative feedback loop to regulate SCAP/SREBP-1 and lipid metabolism

Potential therapies targeting nuclear metabolic regulation in cancer

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