Squalene epoxidase‐induced cholesteryl ester accumulation promotes nasopharyngeal carcinoma development by activating PI3K/AKT signaling

Li, Liming; Wang, Xin; Li, Yan; Xie, Huifen; Chen, Xiangdong

doi:10.1111/cas.14426

Cited by 16 publications

(25 citation statements)

References 16 publications

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“…Thus, the associations between functioning, at least, three quarters of the cholesterol synthesis enzymes and solid cancers progression were found [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ]. Not only overexpression and post-translational activation of enzymes correlated with pathogenic abnormalities, but also a decrease in catalytic function due to down-regulation of expression or pharmacological inhibition (SC5D, NSDHL and EBP).…”

Section: Resultsmentioning

confidence: 99%

Enzymes in the Cholesterol Synthesis Pathway: Interactomics in the Cancer Context

et al. 2021

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A global protein interactome ensures the maintenance of regulatory, signaling and structural processes in cells, but at the same time, aberrations in the repertoire of protein–protein interactions usually cause a disease onset. Many metabolic enzymes catalyze multistage transformation of cholesterol precursors in the cholesterol biosynthesis pathway. Cancer-associated deregulation of these enzymes through various molecular mechanisms results in pathological cholesterol accumulation (its precursors) which can be disease risk factors. This work is aimed at systematization and bioinformatic analysis of the available interactomics data on seventeen enzymes in the cholesterol pathway, encoded by HMGCR, MVK, PMVK, MVD, FDPS, FDFT1, SQLE, LSS, DHCR24, CYP51A1, TM7SF2, MSMO1, NSDHL, HSD17B7, EBP, SC5D, DHCR7 genes. The spectrum of 165 unique and 21 common protein partners that physically interact with target enzymes was selected from several interatomic resources. Among them there were 47 modifying proteins from different protein kinases/phosphatases and ubiquitin-protein ligases/deubiquitinases families. A literature search, enrichment and gene co-expression analysis showed that about a quarter of the identified protein partners was associated with cancer hallmarks and over-represented in cancer pathways. Our results allow to update the current fundamental view on protein–protein interactions and regulatory aspects of the cholesterol synthesis enzymes and annotate of their sub-interactomes in term of possible involvement in cancers that will contribute to prioritization of protein targets for future drug development.

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Section: Resultsmentioning

confidence: 99%

Enzymes in the Cholesterol Synthesis Pathway: Interactomics in the Cancer Context

et al. 2021

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“…8 The oncogenic effect of SQLE in NPC (nasopharyngeal carcinoma) mainly results from cholesteryl ester accumulation and the activation of PI3K/AKT pathway. 25 In prostate cancer, the expression of SQLE is not elevated in prostate cancers in general compared to normal prostatic tissue, however, if the SQLE expression in tumor tissue is elevated by 10%, its odds of lethal cancer increases by 40%. Thus, SQLE can distinguishes tumors at high risk of metastasis.…”

Section: Discussionmentioning

confidence: 98%

“…23 SQLE, a key enzyme of cholesterol biosynthesis, acted as an oncogene and played an important role in many tumors. 24,25 SQLE mRNA expression has been significantly correlated with high-risk ER+ breast cancers. 26 Alteration of SQLE expression modulates cell proliferation and migration by regulating ERK signaling.…”

Section: Discussionmentioning

confidence: 99%

SQLE Mediates Metabolic Reprogramming to Promote LN Metastasis in Castration-Resistant Prostate Cancer

Huang

Dai

et al. 2021

OTT

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Background: Almost all metastatic hormone-sensitive prostate cancers (mHSPC) will develop into metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT). The expression level of squalene monooxygenase (SQLE) is increased in CRPC cells and regulates cholesterol metabolism. This study verified the biological function and mechanisms of SQLE in CRPC. Methods: The expression of SQLE in human prostate cancer cells was overexpressed or silenced and its efficacy on cell survival was determined by the MTS test. Energy metabolism phenotype test was evaluated by XF real-time ATP rate assay, XF cell mitochondrial stress test, XF glycolysis stress test and XF mito fuel flex test. Cell migration and invasion were evaluated by colony formation assays and transwell assays; the expression of mRNA and protein was assessed by RT-qPCR and Western blot, respectively. Moreover, BALB/c nude mice model was performed to evaluate the lymph node metastasis. Results: In our study, we found that the expression level of SQLE was significantly increased in bicalutamide-resistant-C4-2B cells compared to LNCaP cells. SQLE knockdown partly restored the sensitivity of drug-resistant cells to bicalutamide and reduced lymph node metastasis by inhibiting fatty acid oxidation in mitochondria. We also found that terbinafine, the specific inhibitor of SQLE, can enhance the sensitivity of prostate cancer cells to bicalutamide. Conclusion:Our study revealed that SQLE is involved in the progression of castration resistance in CRPC through mediating metabolic reprogramming, presenting SQLE as a new target for the treatment of mCRPC.

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“…Hence, during the anti-cancer treatment, further potent SQLE inhibitors will produce more synergistic effects than terbinafine. Currently, there are several NB-598 derivatives targeting SQLE in human cancer cells 45 , 46 . Our study will provide a potential option for combined treatment with terbinafine and EPZ6438 in HNSCC patients.…”

Section: Discussionmentioning

confidence: 99%

Targeting epigenetic modulation of cholesterol synthesis as a therapeutic strategy for head and neck squamous cell carcinoma

Yang

et al. 2021

Cell Death Dis

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The histone methyltransferase EZH2 silences gene expression via H3 lysine 27 trimethylation and has been recognized as an important antitumour therapeutic target. However, the clinical application of existing EZH2 inhibitors is not satisfactory for the treatment of solid tumours. To discover novel strategies against head and neck squamous cell carcinoma (HNSCC), we performed genomics, metabolomics and RNA omics studies in HNSCC cells treated with EZH2 inhibitors. It was found that EZH2 inhibitors strongly induced the expression of genes in cholesterol synthesis. Through extensive drug screening we found that inhibition of squalene epoxidase (a key enzyme of endogenous cholesterol synthesis) synergistically increased the squalene content and enhanced the sensitivity of HNSCC cells to EZH2 inhibitors. Our findings provide an experimental and theoretical basis for the development of new combinations of EZH2 inhibitors to treat HNSCC.

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Squalene epoxidase‐induced cholesteryl ester accumulation promotes nasopharyngeal carcinoma development by activating PI3K/AKT signaling

Cited by 16 publications

References 16 publications

Enzymes in the Cholesterol Synthesis Pathway: Interactomics in the Cancer Context

Enzymes in the Cholesterol Synthesis Pathway: Interactomics in the Cancer Context

SQLE Mediates Metabolic Reprogramming to Promote LN Metastasis in Castration-Resistant Prostate Cancer

Targeting epigenetic modulation of cholesterol synthesis as a therapeutic strategy for head and neck squamous cell carcinoma

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