Mixed Lineage Luekemia Histone Methyltransferases In Hormonal Regulation Of HOXB9 And Target Gene Regulation

Abstract

Homeobox gene (HOX) genes are evolutionary conserved genes that play important roles in cell differentiation, cell proliferation and embryogenesis. HOX genes bind to the DNA via their homeodomain and act as transcription factors. Of the 39 HOX genes present in human, HOXB9 is known to be a critical player in skeletal and mammary gland development. HOXB9 also regulates renin gene expression which is a critical player in Renin-Angiotensin system. Recent studies also demonstrate that HOXB9 is critical for angiogenesis. I have investigated transcriptional regulation of HOXB9 and its potential biochemical function during cell cycle progression and tumorigenesis. My studies demonstrate that HOXB9 is an estrogen responsive gene. HOXB9 promoter contains multiple estrogen response elements through which they interact with estrogen-receptors and regulate gene expression in presence of estrogen. Mixed lineage leukemia (MLL) family of histone methylases that are key players in gene activation and epigenetics, coordinate with estrogen-receptors during transcriptional activation of HOXB9 in presence of estrogen. Studies also demonstrate that HOXB9 is overexpressed in breast cancer. HOXB9 regulates various cell cycle regulatory genes that includes various Cyclins and p-proteins and regulates cell cycle progression. Overexpression of HOXB9 induces cell cycle arrest in G0/G1 phase and ultimately induces apoptosis. Homeodomain of HOXB9 plays critical roles in transcriptional regulation of cell cycle regulatory genes and cell cycle progression. Further studies demonstrated that HOXB9 overexpression stimulates three-dimensional growth of tumor in colony formation assay. HOXB9 controls the expression of various tumor growth and angiogenic factors via involvement of its homeodomain and thus influences tumor growth. In conclusion, HOXB9 is an estrogen responsive gene and is overexpressed in breast cancer. HOXB9 is a crucial player in cell cycle regulation and tumorigenesis.