Aberrant Lipid Metabolism in Anaplastic Thyroid Carcinoma Reveals Stearoyl CoA Desaturase 1 as a Novel Therapeutic Target

Roemeling, Christina A. Von; Marlow, Laura A.; Pinkerton, Anthony B.; Crist, Angela M.; Miller, James L.; Tun, Han W.; Smallridge, Robert C.; Copland, John A.

doi:10.1210/jc.2014-2764

Cited by 126 publications

(117 citation statements)

References 42 publications

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“…Tomas et al compared mRNA expression in 9 ATCs, 20 PTCs, and 20 normal thyroids in an effort to identify Chernobyl-specific gene expression signatures (data deposited online as GSE29265), but there is no corresponding manuscript at this time. Von Roemeling et al (data deposited online as GSE65144) examined mRNA expression signatures from 12 ATC and 13 normal thyroids (21). They performed extensive validation directed toward alterations in fatty acid metabolism identified by the gene expression study but did not perform gene ontology or pathway clustering.…”

Section: Discussionmentioning

confidence: 99%

Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma

Weinberger

Ponny

et al. 2017

Thyroid

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Background: Anaplastic thyroid carcinoma (ATC) accounts for only 3% of thyroid cancers, yet strikingly, it accounts for almost 40% of thyroid cancer deaths. Currently, no effective therapies exist. In an effort to identify ATC-specific therapeutic targets, we analyzed global gene expression data from multiple studies to identify ATC-specific dysregulated genes. Methods: The National Center for Biotechnology Information Gene Expression Omnibus database was searched for high-throughput gene expression microarray studies from human ATC tissue along with normal thyroid and/or papillary thyroid cancer (PTC) tissue. Gene expression levels in ATC were compared with normal thyroid or PTC using seven separate comparisons, and an ATC-specific gene set common in all seven comparisons was identified. We investigated these genes for their biological functions and pathways. Results: There were three studies meeting inclusion criteria, (including 32 ATC patients, 69 PTC, and 75 normal). There were 259 upregulated genes and 286 downregulated genes in ATC with at least two-fold change in all seven comparisons. Using a five-fold filter, 36 genes were upregulated in ATC, while 40 genes were downregulated. Of the 10 top globally upregulated genes in ATC, 4/10 (MMP1, ANLN, CEP55, and TFPI2) are known to play a role in ATC progression; however, 6/10 genes (TMEM158, CXCL5, E2F7, DLGAP5, MME, and ASPM) had not been specifically implicated in ATC. Similarly, 3/10 (SFTA3, LMO3, and C2orf40) of the most globally downregulated genes were novel in this context, while 7/10 genes (SLC26A7, TG, TSHR, DUOX2, CDH1, PDE8B, and FOXE1) have been previously identified in ATC. We experimentally validated a significant correlation for seven transcription factors (KLF16, SP3, ETV6, FOXC1, SP1, EGFR1, and MAFK) with the ATC-specific genes using microarray analysis of ATC cell lines. Ontology clustering of globally altered genes revealed that ''mitotic cell cycle'' is highly enriched in the globally upregulated gene set (44% of top upregulated genes, p-value <10 -30 ). Conclusions: By focusing on globally altered genes, we have identified a set of consistently altered biological processes and pathways in ATC. Our data are consistent with an important role for M-phase cell cycle genes in ATC, and may provide direction for future studies to identify novel therapeutic targets for this disease.

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Section: Discussionmentioning

confidence: 99%

Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma

Weinberger

Ponny

et al. 2017

Thyroid

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“…When combined with the proteasome inhibitor carfilzomib, the SCD inhibitor MF-438 showed reduced tumor growth in a preclinical model of ATC 35 . In addition, several recent examples of successful combinatorial therapy involving agents targeting lipid metabolism in models of cancer have been established.…”

Section: Stearoyl-coa Desaturase As a Therapeutic Target In Atcmentioning

confidence: 98%

“…These include acetyl-CoA carboxylase alpha (ACC), fatty acid synthase (FASN), and several fatty acid elongase and desaturase enzymes including both human isoforms of stearoyl-CoA desaturase (SCD1, SCD5) 35 . In addition, a variety of proteins whose roles include fatty acid uptake, transport, and metabolism are upregulated including several fatty acid binding proteins (FABP) and solute carrier family 27 (SLC27A) proteins 35 . Taken together, this suggests an increased need for lipid bioavailability in this malignancy.…”

Section: De Novo Lipid Biosynthesis In Atcmentioning

confidence: 99%

“…Of the lipogenic enzymes upregulated in ATC, SCD is the most significantly differentially expressed compared to normal thyroid tissues 35 . Additionally, protein expression of this enzyme is increased in WDTCs including PTC and FTC.…”

Section: Stearoyl-coa Desaturase As a Therapeutic Target In Atcmentioning

confidence: 99%

“…Each of these isoforms demonstrates differential tissue distribution and expression patterns, yet maintains conserved enzymatic function 50 . In ATC, therapeutic and genetic targeted inhibition of SCD enzymatic activity facilitated a robust decrease in cell proliferation and induced cell death where normal thyroid cells remained unaffected 35 . Interestingly, tumor cells derived from well-differentiated lesions demonstrate resistance against SCD inhibition, and suggest a specific vulnerability in the more aggressive thyroid malignancy to this treatment.…”

Section: Stearoyl-coa Desaturase As a Therapeutic Target In Atcmentioning

confidence: 99%

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Targeting lipid metabolism for the treatment of anaplastic thyroid carcinoma

Roemeling¹,

Copland

2015

Expert Opinion on Therapeutic Targets

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Introduction Anaplastic thyroid carcinoma (ATC) is the rarest subtype of thyroid cancer, however it disproportionately accounts for a large percentage of all thyroid cancer related deaths and is considered one of the most lethal solid tumors in humans, having a median survival of only a few months upon diagnosis. While a variety of treatment options are available including surgery, radiation and targeted therapies, response rates are low, due in part to the drug-resistant nature of this disease; therefore, new avenues for therapeutic intervention are surely needed. Recent investigation into the metabolic profile of ATC has revealed a tumor-specific dependency for increased de novo lipogenesis, offering new insight into the molecular mechanisms that govern disease initiation and progression. Areas Covered Herein we summarize known oncogenic signaling pathways and current therapeutic strategies for the treatment of ATC. We further discuss the unique expression pattern of lipid metabolism constituents in this disease. Additionally, the current literature correlating aberrant lipogenesis with carcinogenesis is reviewed, and the implications of targeting this pathway as an innovative approach for treating ATC and other malignancies is discussed. As stearoyl-CoA desaturase (SCD) is the most differentially expressed constituent of lipid metabolism in ATC, an additional focus on this enzyme as a novel therapeutic target is applied. Expert Opinion This section is used to summarize the current research efforts underway in defining the role of lipid metabolism specifically in thyroid carcinoma. Included is a brief summary of lipid metabolism factors for which inhibitors have been generated and are under current investigation as anti-cancer agents. Finally, research limitations regarding the use of these inhibitors against components of this pathway are discussed.

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RUNX2 interacts with SCD1 and activates Wnt/β‐catenin signaling pathway to promote the progression of clear cell renal cell carcinoma

Song

Liu

et al. 2022

Cancer Medicine

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Background: Previous studies have demonstrated that Runt-associated transcription factor 2 (RUNX2) serves as the main transcription factor for osteoblast differentiation and chondrocyte maturation. RUNX2 is related to a variety of tumors, particularly tumor invasion and metastasis, while the expression and molecular mechanisms of RUNX2 in clear cell renal cell carcinoma (ccRCC) keep to be determined. Stearyl CoA desaturase 1 (SCD1), an endoplasmic reticulum fatty acid desaturase, transfers saturated fatty acids to monounsaturated fatty acids, is expressed highly in numerous malignancies. Methods:The Cancer Genome Atlas (TCGA) datebase and Western blot was used to analyzed the mRNA and protein levels of the target gene in ccRCC tissues and adjacent tissues. The proliferation ability of ccRCC cells was tested by colony forming and EdU assay. The migration ability of cells was detected by transwell assay. Immunoprecipitation was utilized to detect protein-protein interaction.Cycloheximide chase assay was used to measure the half-life of SCD1 protein. Results:In this study, the expressions of RUNX2 and SCD1 are increased in ccRCC tissues as well as ccRCC cell lines. Both RUNX2 and SCD1 could promote proliferation and migration in ccRCC cells. Furthermore, RUNX2 could physically interact with SCD1. In addition, the functional degradation and the inactivation of Wnt/β-catenin signaling pathway triggered by the downregulation of RUNX2 could be partly offset by the overexpression of SCD1. Conclusion:The findings indicate that the RUNX2/SCD1 axis may act as a potential therapeutic target via the Wnt/β-catenin signaling pathway of ccRCC. K E Y W O R D Sclear cell renal cell carcinoma, progression, runt-related transcription factor 2, stearyl CoA desaturase 1, Wnt/β-catenin Funding informationNo particular grant that belonged to funding agencies in public, commercial, or nonprofit fields was given to such a study.

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Aberrant Lipid Metabolism in Anaplastic Thyroid Carcinoma Reveals Stearoyl CoA Desaturase 1 as a Novel Therapeutic Target

Cited by 126 publications

References 42 publications

Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma

Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma

Targeting lipid metabolism for the treatment of anaplastic thyroid carcinoma

RUNX2 interacts with SCD1 and activates Wnt/β‐catenin signaling pathway to promote the progression of clear cell renal cell carcinoma

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