title: Histone methylase MLL1 has critical roles in tumor growth and angiogenesis and its knockdown suppresses tumor growth in vivo.
abstract: Mixed lineage leukemias (MLLs) are human histone H3 lysine-4-specific methyl transferases that have critical roles in gene expression, epigenetics and cancer. Herein, we demonstrated that antisense-mediated knockdown of MLL1 induced cell-cycle arrest and apoptosis in cultured cells. Intriguingly, application of MLL1 antisense specifically knocked down MLL1 in vivo and suppressed the growth of xenografted cervical tumor implanted in nude mouse. MLL1 knockdown downregulated various growth and angiogenic factors, such as HIF1α, VEGF and CD31, in tumor tissue affecting tumor growth. MLL1 is overexpressed along the line of vascular network and localized adjacent to endothelial cell layer expressing CD31, indicating potential roles of MLL1 in vasculogenesis. MLL1 is also overexpressed in the hypoxic regions along with HIF1α. Overall, our studies demonstrated that MLL1 is a key factor in hypoxia signaling, vasculogenesis and tumor growth, and its depletion suppresses tumor growth in vivo, indicating its potential in novel cancer therapy.
authors.affiliation: Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, USA.
authors.forename: K I
authors.initials: KI
authors.lastname: Ansari
authors.forename: S
authors.initials: S
authors.lastname: Kasiri
authors.forename: S S
authors.initials: SS
authors.lastname: Mandal
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D005260:Female; D055785:Gene Knockdown Techniques; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D015398:Signal Transduction / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000098:blood supply* / Q000201:enzymology / Q000235:genetics / Q000473:pathology*
chemical_list: C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase