hSET1: a novel approach for colon cancer therapy.
Histone-methyl transferases (HMTs) are key enzymes that post-translationally modify histones, and serve key role in gene expression, epigenetic regulation, and as determinants of survival in malignant cells. Recent studies have shed light on the role of hSET1 which is a key element of highly conserved multi-protein HMT complex that catalyze methylation of histone H3 lysine 4 (H3K4) regulating expression of specific proteins important for the malignant phenotype. To understand the importance of differential expression of H3K4 HMTs in cancer, we specifically down-regulated hSET1 the only H3K4 specific histone-methyl transferase present in yeast as well as in human that is directly involved in gene expression. hSET1 has been shown to be differentially over-expressed in the malignant cells as compared to the normal cells at the RNA as well as protein level. In a wide array of normal and malignant cells it has been demonstrated that phosphorothioate antisense against hSET1 (DN5) caused selective and differential apoptosis in malignant cells only while the normal cells remains unaffected. Down-regulation of hSET1 leads to rapid and complete regression of SW480 colon xenograft in mice model. These findings demonstrate that hSET1 over-expression promotes cell proliferation and cancer cell survival, and may be a novel target for cancer therapy.
Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Sushma
S
Yadav
Jyotsana
J
Singhal
Sharad S
SS
Singhal
Sanjay
S
Awasthi
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D054735:Phosphorothioate Oligonucleotides / Q000494:pharmacology; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D011495:Histone-Lysine N-Methyltransferase; C526068:Setd1A protein, human