title: Histone methyltransferase KMT1A restrains entry of alveolar rhabdomyosarcoma cells into a myogenic differentiated state.
abstract: Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric muscle cancer, which arrested during the process of skeletal muscle differentiation. In muscle myoblast cells, ectopic expression of the histone H3 lysine 9 (H3K9) methytransferase KMT1A blocks differentiation by repressing a myogenic gene expression program. In this study, we tested the hypothesis that activation of a KMT1A-mediated program of transcriptional repression prevents ARMS cells from differentiating. We investigated whether KMT1A represses the expression of differentiation-associated genes in ARMS cells, thereby blocking muscle differentiation. Our results show that expression of KMT1A is induced in human ARMS cancer cell lines when cultured under differentiation-permissible conditions. shRNA-mediated knockdown of KMT1A decreased anchorage dependent and independent cell proliferation and tumor xenograft growth, increased expression of differentiation-associated genes, and promoted the appearance of a terminally differentiated-like phenotype. Finally, shRNA-directed KMT1A knockdown restored the impaired transcriptional activity of the myogenic regulator MyoD. Together, our results suggested that high levels of KMT1A in ARMS cells under differentiation conditions impairs MyoD function, thereby arresting myogenic differentiation in these tumor cells. Thus, targeting KMT1A may be a novel strategy for the treatment of this disease.
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
authors.forename: Min-Hyung
authors.initials: MH
authors.lastname: Lee
authors.forename: Mathivanan
authors.initials: M
authors.lastname: Jothi
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
authors.forename: Asoke K
authors.initials: AK
authors.lastname: Mal
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002648:Child; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D006801:Humans; D051379:Mice; D017570:MyoD Protein / Q000378:metabolism; D018008:Myogenin / Q000235:genetics; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D018232:Rhabdomyosarcoma, Alveolar / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous
chemical_list: D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D018008:Myogenin; D034741:RNA, Small Interfering; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase