Sphingolipids and expression regulation of genes in cancer

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 treatment outcome. More than ten sphingolipids and glycosphingolipids selectively mediate expressions of approximate fifty 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.

Carnitine palmitoyltransferase 1C: From cognition to cancer

“…Although the mechanisms by which ceramide regulates BSX expression are unclear, two sets of observations are relevant: i) ceramide forms gel-phase platforms in the plasma membrane and recruits target proteins for specific signaling that can regulate gene expression [53,54]; and ii) ceramides or their soluble derivatives, such as ceramide-1-phosphate and sphingosine, bind transcription factors and modulate target gene expression [55][56][57][58].…”

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

“…These membrane lipids do not only function as structural components of the cell membrane, but they also possess important roles in signal transduction as second messengers and in vital cellular processes such as differentiation, migration, apoptosis, cell proliferation, cell cycle arrest, senescence, and inflammation [5][6][7][8]. The basic structure of all sphingolipids consists of up to three components: a sphingoid backbone (such as sphingosine, 1,3-dihydroxy-2-aminoalkane and its derivatives), an amide-linked long-chain fatty acid tail, and several distinct modifications of the head group [9,10]. The head groups define the various sphingolipid classes, with a hydroxyl group found in ceramides; phosphorylcholine, in sphingomyelin (SM); and carbohydrates, in the various glycosphingolipids [11,12].…”

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

“…1). Some of those species play opposing roles while some others are working in concert for the similar outcome; and cellular fate is determined by their interactions and ratios in the cell [4][5][6].…”