Abnormal DNA methylation of CD133 in colorectal and glioblastoma tumors.
Much recent effort has focused on identifying and characterizing cellular markers that distinguish tumor propagating cells (TPC) from more differentiated progeny. We report here an unusual promoter DNA methylation pattern for one such marker, the cell surface antigen CD133 (Prominin 1). This protein has been extensively used to enrich putative cancer propagating stem-like cell populations in epithelial tumors and, especially, glioblastomas. We find that, within individual cell lines of cultured colon cancers and glioblastomas, the promoter CpG island of CD133 is DNA methylated, primarily, in cells with absent or low expression of the marker protein, whereas lack of such methylation is evident in purely CD133+ cells. Differential histone modification marks of active versus repressed genes accompany these DNA methylation changes. This heterogeneous CpG island DNA methylation status in the tumors is unusual in that other DNA hypermethylated genes tested in such cultures preserve their methylation patterns between separated CD133+ and CD133- cell populations. Furthermore, the CD133 DNA methylation seems to constitute an abnormal promoter signature because it is not found in normal brain and colon but only in cultured and primary tumors. Thus, the DNA methylation is imposed on the transition between the active versus repressed transcription state for CD133 only in tumors. Our findings provide additional insight for the dynamics of aberrant DNA methylation associated with aberrant gene silencing in human tumors.
Yi
Joo Mi
JM
Cancer Biology Division, Johns Hopkins Kimmel Cancer Center, USA.
Tsai
Hsing-Chen
HC
Glöckner
Sabine C
SC
Lin
Steven
S
Ohm
Joyce E
JE
Easwaran
Hari
H
James
C David
CD
Costello
Joseph F
JF
Riggins
Gregory
G
Eberhart
Charles G
CG
Laterra
John
J
Vescovi
Angelo L
AL
Ahuja
Nita
N
Herman
James G
JG
Schuebel
Kornel E
KE
Baylin
Stephen B
SB
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018938:Caco-2 Cells; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D000077209:Decitabine; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine