Tropomyosin-1, a novel suppressor of cellular transformation is downregulated by promoter methylation in cancer cells.
Tropomyosins (TMs) are a family of microfilament binding proteins, which are suppressed in the transformed cells. We have investigated the mechanism of suppression of TMs, in particular that of tropomyosin-1 (TM1), in breast cancer cells. Inhibition of DNA methyl transferase with 5-aza-2'-deoxycytidine (AZA) alone did not induce TM1 expression. However, combined treatment of trichostatin A (TSA) and AZA resulted in readily detectable expression of TM1, but not that of other TM isoforms. Upregulation of TM1 expression paralleled with the reemergence of TM1 containing microfilaments, and in abolition of anchorage-independent growth. The synergistic action of AZA and TSA in reactivation of TM1 gene was also evident in ras-transformed fibroblasts. These data, for the first time, show that hypermethylation of TM1 gene and chromatin remodeling are the predominant mechanisms by which TM1 expression is downregulated in breast cancer cells.
Bharadwaj
Shantaram
S
Department of General Surgery, Medical Center Boulevard, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Prasad
G L
GL
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D019175:DNA Methylation; D000077209:Decitabine; D015536:Down-Regulation; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D011401:Promoter Regions, Genetic; D014335:Tropomyosin / Q000096:biosynthesis* / Q000235:genetics*; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D002843:Chromatin; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C490775:TPM1 protein, human; C097163:Tm2 protein, Drosophila; D014335:Tropomyosin; C012589:trichostatin A; D000077209:Decitabine; D006655:Histone Deacetylases; D001374:Azacitidine