Role of <i>de novo</i> cholesterol synthesis enzymes in cancer

Yang, Jie; Wang, Lihua; Jia, Renbing

doi:10.7150/jca.38598

Cited by 47 publications

(47 citation statements)

References 89 publications

(82 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Cholesterol metabolism is often reprogrammed in cancer cells [ 48 ]. Our findings demonstrated that the reduced accumulation of cholesterol metabolism-related intermediates in renal cancer tissue was associated with downregulation of the low-density lipoprotein receptor (LDLR) gene and correlated with the serum total cholesterol levels.…”

Section: Discussionmentioning

confidence: 99%

Integration of Lipidomics and Transcriptomics Reveals Reprogramming of the Lipid Metabolism and Composition in Clear Cell Renal Cell Carcinoma

et al. 2020

View full text Add to dashboard Cite

Clear cell renal cell carcinoma (ccRCC) is fundamentally a metabolic disease. Given the importance of lipids in many cellular processes, in this study we delineated a lipidomic profile of human ccRCC and integrated it with transcriptomic data to connect the variations in cancer lipid metabolism with gene expression changes. Untargeted lipidomic analysis was performed on 20 ccRCC and 20 paired normal tissues, using LC-MS and GC-MS. Different lipid classes were altered in cancer compared to normal tissue. Among the long chain fatty acids (LCFAs), significant accumulations of polyunsaturated fatty acids (PUFAs) were found. Integrated lipidomic and transcriptomic analysis showed that fatty acid desaturation and elongation pathways were enriched in neoplastic tissue. Consistent with these findings, we observed increased expression of stearoyl-CoA desaturase (SCD1) and FA elongase 2 and 5 in ccRCC. Primary renal cancer cells treated with a small molecule SCD1 inhibitor (A939572) proliferated at a slower rate than untreated cancer cells. In addition, after cisplatin treatment, the death rate of tumor cells treated with A939572 was significantly greater than that of untreated cancer cells. In conclusion, our findings delineate a ccRCC lipidomic signature and showed that SCD1 inhibition significantly reduced cancer cell proliferation and increased cisplatin sensitivity, suggesting that this pathway can be involved in ccRCC chemotherapy resistance.

show abstract

Section: Discussionmentioning

confidence: 99%

Integration of Lipidomics and Transcriptomics Reveals Reprogramming of the Lipid Metabolism and Composition in Clear Cell Renal Cell Carcinoma

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Especially fast growing tumor cells require increased amounts of cholesterol as essential components for membrane buildup, as well as for synthesis of signaling molecules. Accordingly, up-regulation of enzymes for cholesterol biosynthesis causing an increase of cellular cholesterol production is essential for tumorigenesis and tumor progression [ 39 , 40 , 41 , 42 ]. Furthermore, analysis of the expression of cholesterol synthesis genes in diverse cancers using the Cancer Genome Atlas (TCGA) also indicated deregulation of cholesterol homeostasis as an important factor in cancer development [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

(Phospho)proteomic Profiling of Microsatellite Unstable CRC Cells Reveals Alterations in Nuclear Signaling and Cholesterol Metabolism Caused by Frameshift Mutation of NMD Regulator UPF3A

Michalak

Katzenmaier

Roeckel

et al. 2020

IJMS

View full text Add to dashboard Cite

DNA mismatch repair-deficient colorectal cancers (CRCs) accumulate numerous frameshift mutations at repetitive sequences recognized as microsatellite instability (MSI). When coding mononucleotide repeats (cMNRs) are affected, tumors accumulate frameshift mutations and premature termination codons (PTC) potentially leading to truncated proteins. Nonsense-mediated RNA decay (NMD) can degrade PTC-containing transcripts and protect from such faulty proteins. As it also regulates normal transcripts and cellular physiology, we tested whether NMD genes themselves are targets of MSI frameshift mutations. A high frequency of cMNR frameshift mutations in the UPF3A gene was found in MSI CRC cell lines (67.7%), MSI colorectal adenomas (55%) and carcinomas (63%). In normal colonic crypts, UPF3A expression was restricted to single chromogranin A-positive cells. SILAC-based proteomic analysis of KM12 CRC cells revealed UPF3A-dependent down-regulation of several enzymes involved in cholesterol biosynthesis. Furthermore, reconstituted UPF3A expression caused alterations of 85 phosphosites in 52 phosphoproteins. Most of them (38/52, 73%) reside in nuclear phosphoproteins involved in regulation of gene expression and RNA splicing. Since UPF3A mutations can modulate the (phospho)proteomic signature and expression of enzymes involved in cholesterol metabolism in CRC cells, UPF3A may influence other processes than NMD and loss of UPF3A expression might provide a growth advantage to MSI CRC cells.

show abstract

“…Cells usually obtain cholesterol via different mechanisms including direct synthesis via the transcriptional activity of SREBPs, which promote the transcription of enzymes involved in cholesterol and fatty acid biosynthesis [i.e., 3-hydroxy-3methylglutaryl-coenzyme A reductase (HMG-CoA) reductase] (94,95). In this regard, the recent use of HMG-CoA inhibitors (Statins) to block the mevalonate pathway and cholesterol de novo biosynthesis showed promising results (96).…”

Section: Lxrs As Regulators Of Lipid Metabolism Cancer Progression mentioning

confidence: 99%

Liver X Receptors: Regulators of Cholesterol Metabolism, Inflammation, Autoimmunity, and Cancer

et al. 2020

View full text Add to dashboard Cite

The interplay between cellular stress and immune response can be variable and sometimes contradictory. The mechanisms by which stress-activated pathways regulate the inflammatory response to a pathogen, in autoimmunity or during cancer progression remain unclear in many aspects, despite our recent knowledge of the signalling and transcriptional pathways involved in these diseases. In this context, over the last decade many studies demonstrated that cholesterol metabolism is an important checkpoint for immune homeostasis and cancer progression. Indeed, cholesterol is actively metabolized and can regulate, through its mobilization and/or production of active derivatives, many aspects of immunity and inflammation. Moreover, accumulation of cholesterol has been described in cancer cells, indicating metabolic addiction. The nuclear receptors liver-X-receptors (LXRs) are important regulators of intracellular cholesterol and lipids homeostasis. They have also key regulatory roles in immune response, as they can regulate inflammation, innate and adaptive immunity. Moreover, activation of LXRs has been reported to affect the proliferation and survival of different cancer cell types that show altered metabolic pathways and accumulation of cholesterol. In this minireview we will give an overview of the recent understandings about the mechanisms through which LXRs regulate inflammation, autoimmunity, and cancer, and the therapeutic potential for future treatment of these diseases through modulation of cholesterol metabolism.

show abstract

Role of de novo cholesterol synthesis enzymes in cancer

Cited by 47 publications

References 89 publications

Integration of Lipidomics and Transcriptomics Reveals Reprogramming of the Lipid Metabolism and Composition in Clear Cell Renal Cell Carcinoma

Integration of Lipidomics and Transcriptomics Reveals Reprogramming of the Lipid Metabolism and Composition in Clear Cell Renal Cell Carcinoma

(Phospho)proteomic Profiling of Microsatellite Unstable CRC Cells Reveals Alterations in Nuclear Signaling and Cholesterol Metabolism Caused by Frameshift Mutation of NMD Regulator UPF3A

Liver X Receptors: Regulators of Cholesterol Metabolism, Inflammation, Autoimmunity, and Cancer

Contact Info

Product

Resources

About