Global identification of genes targeted by DNMT3b for epigenetic silencing in lung cancer.
The maintenance cytosine DNA methyltransferase DNMT1 and de novo methyltransferase DNMT3b cooperate to establish aberrant DNA methylation and chromatin complexes to repress gene transcription during cancer development. The expression of DNMT3b was constitutively increased 5-20-fold in hTERT/CDK4-immortalized human bronchial epithelial cells (HBECs) before treatment with low doses of tobacco carcinogens. Overexpression of DNMT3b increased and accelerated carcinogen-induced transformation. Genome-wide profiling of transformed HBECs identified 143 DNMT3b-target genes, many of which were transcriptionally regulated by the polycomb repressive complex 2 (PRC2) complex and silenced through aberrant methylation in non-small-cell lung cancer cell lines. Two genes studied in detail, MAL and OLIG2, were silenced during transformation, initially through enrichment for H3K27me3 and H3K9me2, commonly methylated in lung cancer, and exert tumor suppressor effects in vivo through modulating cancer-related pathways. Re-expression of MAL and OLIG2 to physiological levels dramatically reduced the growth of lung tumor xenografts. Our results identify a key role for DNMT3b in the earliest stages of initiation and provide a comprehensive catalog of genes targeted for silencing by this methyltransferase in non-small-cell lung cancer.
Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
I
I
Teneng
Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
C S
CS
Tellez
Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
M A
MA
Picchi
Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
D M
DM
Klinge
Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
C M
CM
Yingling
Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
A M
AM
Snider
Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
Y
Y
Liu
Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
S A
SA
Belinsky
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D002273:Carcinogens / Q000633:toxicity; D002843:Chromatin / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D000076104:Oligodendrocyte Transcription Factor 2; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis; D019098:Telomerase / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000097584:DNA Methyltransferase 3B
D051792:Basic Helix-Loop-Helix Proteins; D002273:Carcinogens; D002843:Chromatin; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D063151:Polycomb Repressive Complex 2; D017472:Receptors, Interleukin-1; D019098:Telomerase; D000097584:DNA Methyltransferase 3B; C405708:OLIG2 protein, human; C434984:TIRAP protein, human; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; C509186:TERT protein, human