Contribution of polycomb homologues Bmi-1 and Mel-18 to medulloblastoma pathogenesis.
Bmi-1 and Mel-18 are structural homologues that belong to the Polycomb group of transcriptional regulators and are believed to stably maintain repression of gene expression by altering the state of chromatin at specific promoters. While a number of clinical and experimental observations have implicated Bmi-1 in human tumorigenesis, the role of Mel-18 in cancer cell growth has not been investigated. We report here that short hairpin RNA-mediated knockdown of either Bmi-1 or Mel-18 in human medulloblastoma DAOY cells results in the inhibition of proliferation, loss of clonogenic survival, anchorage-independent growth, and suppression of tumor formation in nude mice. Furthermore, overexpression of both Bmi-1 and Mel-18 significantly increases the clonogenic survival of Rat1 fibroblasts. In contrast, stable downregulation of Bmi-1 or Mel-18 alone does not affect the growth of normal human WI38 fibroblasts. Proteomics-based characterization of Bmi-1 and Mel-18 protein complexes isolated from cancer cells revealed substantial similarities in their respective compositions. Finally, gene expression analysis identified a number of cancer-relevant pathways that may be controlled by Bmi-1 and Mel-18 and also showed that these Polycomb proteins regulate a set of common gene targets. Taken together, these results suggest that Bmi-1 and Mel-18 may have overlapping functions in cancer cell growth.
Wiederschain
Dmitri
D
Oncology Research, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
Chen
Lin
L
Johnson
Brett
B
Bettano
Kimberly
K
Jackson
Dowdy
D
Taraszka
John
J
Wang
Y Karen
YK
Jones
Michael D
MD
Morrissey
Michael
M
Deeds
James
J
Mosher
Rebecca
R
Fordjour
Paul
P
Lengauer
Christoph
C
Benson
John D
JD
D000818:Animals; D016923:Cell Death; D049109:Cell Proliferation; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014183:Transplantation, Heterologous
C069077:BMI1 protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C489348:PCGF2 protein, human; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1