Squalene epoxidase as a promising metabolic target in cancer treatment

Cirmena, Gabriella; Franceschelli, Paola; Isnaldi, Edoardo; Ferrando, Lorenzo; Mariano, Marilena De; Ballestrero, Alberto; Zoppoli, Gabriele

doi:10.1016/j.canlet.2018.03.034

Cited by 58 publications

(54 citation statements)

References 92 publications

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“…Cancer is one of the most dreadful diseases that mankind faces, and it generally manifests as uncontrolled growth of cells that can metastasize into other parts of the body. A wide range of studies have shown that the regular consumption of squalene may inhibit the proliferation of tumor cells, especially those of the breast, pancreas, colon, and melanoma, the activation of which depends on the prenylation of proteins (Newmark, 1997; Cirmena et al, 2018).…”

Section: Potential Applications Of Squalenementioning

confidence: 99%

Engineering Strategies in Microorganisms for the Enhanced Production of Squalene: Advances, Challenges and Opportunities

Gohil

Bhattacharjee

Khambhati

et al. 2019

Front. Bioeng. Biotechnol.

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The triterpene squalene is a natural compound that has demonstrated an extraordinary diversity of uses in pharmaceutical, nutraceutical, and personal care industries. Emboldened by this range of uses, novel applications that can gain profit from the benefits of squalene as an additive or supplement are expanding, resulting in its increasing demand. Ever since its discovery, the primary source has been the deep-sea shark liver, although recent declines in their populations and justified animal conservation and protection regulations have encouraged researchers to identify a novel route for squalene biosynthesis. This renewed scientific interest has profited from immense developments in synthetic biology, which now allows fine-tuning of a wider range of plants, fungi, and microorganisms for improved squalene production. There are numerous naturally squalene producing species and strains; although they generally do not make commercially viable yields as primary shark liver sources can deliver. The recent advances made toward improving squalene output from natural and engineered species have inspired this review. Accordingly, it will cover in-depth knowledge offered by the studies of the natural sources, and various engineering-based strategies that have been used to drive the improvements in the pathways toward large-scale production. The wide uses of squalene are also discussed, including the notable developments in anti-cancer applications and in augmenting influenza vaccines for greater efficacy.

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Section: Potential Applications Of Squalenementioning

confidence: 99%

Engineering Strategies in Microorganisms for the Enhanced Production of Squalene: Advances, Challenges and Opportunities

Gohil

Bhattacharjee

Khambhati

et al. 2019

Front. Bioeng. Biotechnol.

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“…In conclusion, we identified key serine residues, Ser-59, Ser-61, Ser-83, and Ser-87, which are likely to act as serine ubiquitination sites governing the cholesterol-accelerated degradation of SM, a rate-limiting enzyme important in disease (77)(78)(79) and biotechnology (80,81). This work advances our understanding of degron architecture and provides a model whereby excess cholesterol deforms the SM N100 amphipathic helix, adding to the disorder of the flanking regions where the key serines reside, allowing these residues to be ubiquitinated by MARCH6 (Fig.…”

Section: Serine Ubiquitination and Cholesterol Regulationmentioning

confidence: 84%

Non-canonical ubiquitination of the cholesterol-regulated degron of squalene monooxygenase

Chua¹,

Hart‐Smith²,

Brown

2019

Journal of Biological Chemistry

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Squalene monooxygenase (SM) is a rate-limiting enzyme in cholesterol synthesis. The region comprising the first 100 amino acids, termed SM N100, represents the shortest cholesterol-responsive degron and enables SM to sense excess cholesterol in the endoplasmic reticulum (ER) membrane. Cholesterol accelerates the ubiquitination of SM by membrane-associated ring-CH type finger 6 (MARCH6), a key E3 ubiquitin ligase involved in ER-associated degradation. However, the ubiquitination site required for cholesterol regulation of SM N100 is unknown. Here, we used SM N100 fused to GFP as a model degron to recapitulate cholesterol-mediated SM degradation and show that neither SM lysine residues nor the N terminus impart instability. Instead, we discovered four serines (Ser-59, Ser-61, Ser-83, and Ser-87) that are critical for cholesterol-accelerated degradation, with MS analysis confirming Ser-83 as a ubiquitination site. Notably, these two clusters of closely spaced serine residues are located in disordered domains flanking a 12-amino acid-long amphipathic helix (residues Gln-62–Leu-73) that together confer cholesterol responsiveness. In summary, our findings reveal the degron architecture of SM N100, introducing the role of non-canonical ubiquitination sites and deepening our molecular understanding of how SM is degraded in response to cholesterol.

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“…This work provides mechanistic insights into the regulation of human SM, an essential rate-limiting enzyme of cholesterol synthesis that is implicated in disease (32)(33)(34)(35). The substrate of SM, squalene, is known to bind to the catalytic domain of SM.…”

Section: Discussionmentioning

confidence: 99%

A key mammalian cholesterol synthesis enzyme, squalene monooxygenase, is allosterically stabilized by its substrate

Yoshioka

Coates

Chua

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Cholesterol biosynthesis is a high-cost process and, therefore, tightly regulated by both transcriptional and posttranslational negative feedback mechanisms in response to the level of cellular cholesterol. Squalene monooxygenase (SM, also known as squalene epoxidase or SQLE) is a rate-limiting enzyme in the cholesterol biosynthetic pathway and catalyzes epoxidation of squalene. The stability of SM is negatively regulated by cholesterol via its N-terminal regulatory domain (SM-N100). In this study, using a SM-luciferase fusion reporter cell line, we performed a chemical genetics screen that identified inhibitors of SM itself as up-regulators of SM. This effect was mediated through the SM-N100 region, competed with cholesterol-accelerated degradation, and required the E3 ubiquitin ligase MARCH6. However, up-regulation was not observed with statins, well-established cholesterol biosynthesis inhibitors, and this pointed to the presence of another mechanism other than reduced cholesterol synthesis. Further analyses revealed that squalene accumulation upon treatment with the SM inhibitor was responsible for the up-regulatory effect. Using photoaffinity labeling, we demonstrated that squalene directly bound to the N100 region, thereby reducing interaction with and ubiquitination by MARCH6. Our findings suggest that SM senses squalene via its N100 domain to increase its metabolic capacity, highlighting squalene as a feedforward factor for the cholesterol biosynthetic pathway.

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Squalene epoxidase as a promising metabolic target in cancer treatment

Cited by 58 publications

References 92 publications

Engineering Strategies in Microorganisms for the Enhanced Production of Squalene: Advances, Challenges and Opportunities

Engineering Strategies in Microorganisms for the Enhanced Production of Squalene: Advances, Challenges and Opportunities

Non-canonical ubiquitination of the cholesterol-regulated degron of squalene monooxygenase

A key mammalian cholesterol synthesis enzyme, squalene monooxygenase, is allosterically stabilized by its substrate

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