Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
Oncogene. 2015 Jan 29;34(5):621-30. doi: 10.1038/onc.2013.580. Epub 2014 Jan 27.
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.
维持性胞嘧啶 DNA 甲基转移酶 DNMT1 和从头甲基转移酶 DNMT3b 合作，在癌症发展过程中建立异常的 DNA 甲基化和染色质复合物，从而抑制基因转录。在低剂量烟草致癌剂处理之前，hTERT/CDK4 永生化的人支气管上皮细胞（HBEC）中 DNMT3b 的表达持续增加 5-20 倍。DNMT3b 的过表达增加并加速了致癌物诱导的转化。转化的 HBEC 的全基因组分析确定了 143 个 DNMT3b 靶基因，其中许多基因受多梳抑制复合物 2（PRC2）复合物转录调控，并通过非小细胞肺癌细胞系中的异常甲基化沉默。详细研究的两个基因，MAL 和 OLIG2，在转化过程中被沉默，最初通过富集 H3K27me3 和 H3K9me2 起作用，这两种修饰在肺癌中很常见，并通过调节癌症相关途径在体内发挥肿瘤抑制作用。MAL 和 OLIG2 的生理水平的重新表达显著降低了肺癌肿瘤异种移植物的生长。我们的结果确定了 DNMT3b 在起始的最早阶段的关键作用，并提供了非小细胞肺癌中该甲基转移酶沉默靶基因的综合目录。
