Epigenetic DNA-methylation regulation of genes coding for lipid raft-associated components: A role for raft proteins in cell transformation and cancer progression (Review)

Abstract

Abstract. Metastatic progression is the cause of most cancer deaths. Host tumour cell separation (fission) is accompanied by simultaneous acquisition of migrating capability of cancer cells, remodeling of cellular architecture and effective 'homing' in body host environment. Cell remodeling involves cytoskeletal protein-protein and lipid-protein interaction together with altered signaling. Alteration of signaling in tumour cells may affect expression of many genes also by DNAmethylation/demethylation. This would alter the steady-state intracellular level of structural proteins or metabolic enzymes, and notably enzymes involved in the biosynthesis of lipids, affecting the composition of membranes. Lipid rafts are small, heterogeneous, highly dynamic, sterol-and sphingolipidenriched domains that compartmentalize cellular processes. Small rafts can be stabilized to form larger platforms through protein-protein and protein-lipid interactions. Lipid rafts play an important role in intracellular protein transport, membrane fusion and trans-cytosis, also being platforms for cell surface antigens and adhesion molecules which are crucial for cell activation, polarization and signaling. Detachment of individual tumour cells from the host tumour lump requires lipid-protein-lipid raft (LPLR) reordering. Lipid rafts are also involved in angiogenesis and local invasion, which occurs within the host tumour vicinity by exchange of enzymes, cytokines and motility factors that modify the surrounding extracellular matrix (ECM). Many cell surface adhesion, ECM, and signaling proteins (such as E-cadherin, catenin, CD44, MMP-9 and caveolin-1) are known to be absent or reduced following gene promoter-CpG-island hypermethylation in mid-stage growing tumours, but re-expressed (by gene promoterm CpG-DNA demethylation) in carcinomas such as metastasized lung, prostate and sarcomas. The recent research acquisitions on lipid rafts have tremendous implications in understanding the genetic and biochemical bases of metastatic diffusion of cancer.

Lipid rafts: signaling and sorting platforms of cells and their roles in cancer

“…The expression of uPAR is cancer stage specific [46]. uPAR is an adhesion receptor for vitronectin and also interacts with integrin b-chains.…”

“…Proteolysis of extracellular matrix proteins modifies integrin-mediated anchorage, focal adhesion and cytoskeletal archi tecture, thereby triggering signaling molecules such as FAK [47] and motility factors such as autocrine motility factor/phosphohexose isomerase PHI [48]. It has been shown that matrix metalloproteinase and uPAR expression is controlled at the transcription level by DNA methylation and demethylation [46].…”

Caveolin-1 as a potential high-risk prostate cancer biomarker

“…These membranes are involved in receptor-independent endocytosis. Caveolae are microdomains of lipid rafts, which are rich in sphingolipids and cholesterol and play an essential role in the degradation of cholesterol (14). However, they also participate in transmembrane signalling.…”

Knockdown of FLOT1 Impairs Cell Proliferation and Tumorigenicity in Breast Cancer through Upregulation of FOXO3a

“…Many proteins, such as H-Ras, caveolin-1, CD44, Fas, Fas-associated death domain protein, uPAR, epidermal growth factor receptor (EGFR), integrins, and catenins, conduct their function in lipid rafts (3,4). Although being important structural components for delivering lipids and proteins, lipid rafts have also been reported by numerous studies to be involved in the development and progression of cancer (5,6). For instance, the cholesterol-enriched lipid raft, containing proteins such as caveolins, CD44, and members of the receptor tyrosine kinase family, induces cell transformation, tumor progression, angiogenesis, and metastasis.…”

“…For instance, the cholesterol-enriched lipid raft, containing proteins such as caveolins, CD44, and members of the receptor tyrosine kinase family, induces cell transformation, tumor progression, angiogenesis, and metastasis. The sphingolipidenriched lipid raft, containing FAS, FASL, and death-inducing signaling complex proteins prevent cells from apoptosis (5,6). Therefore, lipid rafts have been recently suggested to be new therapeutic targets and intervention strategies against cancer (7,8).…”