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Review
. 2011 Jan;50(1):104-14.
doi: 10.1016/j.plipres.2010.10.003. Epub 2010 Oct 21.

Sphingolipids and Expression Regulation of Genes in Cancer

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Free PMC article
Review

Sphingolipids and Expression Regulation of Genes in Cancer

Gauri A Patwardhan et al. Prog Lipid Res. .
Free PMC article

Abstract

Sphingolipids including glycosphingolipids have myriad effects on cell functions and affect cancer in aspects of tumorigenesis, metastasis and tumor response to treatments. Bioactive ones like ceramide, sphingosine 1-phosphate and globotriaosylceramide initiate and process cellular signaling to alter cell behaviors immediately responding to oncogenic stress or treatment challenges. Recent studies pinpoint that sphingolipid-mediated gene expression has long and profound impacts on cancer cells, and these play crucial roles in tumor progression and in treatment outcome. More than 10 sphingolipids and glycosphingolipids selectively mediate expressions of approximately 50 genes including c-myc, p21, c-fos, telomerase reverse transcriptase, caspase-9, Bcl-x, cyclooxygenase-2, matrix metalloproteinases, integrins, Oct-4, glucosylceramide synthase and multidrug-resistant gene 1. By diverse functions of these genes, sphingolipids enduringly affect cellular processes of mitosis, apoptosis, migration, stemness of cancer stem cells and cellular resistance to therapies. Mechanistic studies indicate that sphingolipids regulate particular gene expression by modulating phosphorylation and acetylation of proteins that serve as transcription factors (β-catenin, Sp1), repressor of transcription (histone H3), and regulators (SRp30a) in RNA splicing. Disclosing molecular mechanisms by which sphingolipids selectively regulate particular gene expression, instead of other relevant ones, requires understanding of the exact roles of individual lipid instead of a group, the signaling pathways that are implicated in and interaction with proteins or other lipids in details. These studies not only expand our knowledge of sphingolipids, but can also suggest novel targets for cancer treatments.

Figures

Fig. 1
Fig. 1
Basic structures and classification of sphingolipids. In mammals, the prevalent sphingoid base is sphingosine which has a chain length of 18 carbon atoms and E-double bond between C4 and C5.
Fig. 2
Fig. 2
Biosynthetic pathway of sphingolipids that mediate expressions of genes associated with cellular processes in cancer. Dotted arrows indicate particular sphingolipids that up- or down-regulate gene expression (Up, Down). CerS, ceramide synthase; GCS, glucosylceramide synthase; LacCerS, lactosylceramide synthase; Gb3S, globotriaosylceramide synthase; GCase, glucosylceramide β-glucosidase; GLA, α-galactosidase A; GALC, galactosylceramidase; SphK, sphingosine kinase; SPPase, sphingosine phosphate phosphatase; CerK, ceramide kinase; CPPase, ceramide phosphate phosphatase; GM3S, GM3 synthase.
Fig. 3
Fig. 3
Ceramide and globo-series GSLs upregulate GCS and MDR1 leading cell resistant to anticancer drugs via protein kinase cascades and recruitment of transcription factors. Ceramide generated by de novo synthesis in response to stress transactivates GCS expression possibly by the MAPK or PKC cascades and the Sp1 transcription factor; globo-series GSLs (Gb3, Gb5) interact with lipids/protein on GEMs and activate cSrc-GSK cascade, consequently increase recruitment of β-catenin/Tcf-4 to upregulate MDR1. Mitogen-activated protein kinase; GEMs, GSL-enriched microdomains; GSK, glycogen synthase kinase-3.
Fig. 4
Fig. 4
Cellular ceramide upregulates apoptotic Bcl-x or caspase-9 expression via activation of PP1 and RNA splicing. Ceramide generated in the de novo synthesis pathway responding to gemcitabine activates nuclear PP1 and increases the amounts of non-phosphorylated SRp30a that binds to the splicing sites of pre-mRNA of Bcl-x or caspase-9. These will increase the expression of Bcl-x (L) or the caspase-9b isoform that is the pro-apoptosis. PP1, protein phosphatase 1.
Fig. 5
Fig. 5
Nuclear sphingosine 1-phosphate upregulates p21 or c-fos expression via histone H3 acetylation and release of repressor complex. Nuclear SphK2 that is located with HDA1 and HDA2 produces S1P in response to PKC activation. S1P bound to HDAC1 or HDAC2 and prevents their deacetylation on histone H3 and increases the release of repressor complex from promoter region to express p21 or c-fos. SphK2, sphingosine kinase 2; Sph, sphingosine; AC, acetyl; HDAC1, histone deacetylase 1; HDAC2, histone deacetylase.

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