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

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 DNA-methylation/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 sphingolipid-enriched 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 promoter-mCpG-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.