The c-Myc oncogene directly induces the H19 noncoding RNA by allele-specific binding to potentiate tumorigenesis
The c-Myc oncogene directly induces the H19 noncoding RNA by allele-specific binding to potentiate tumorigenesis
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DOI：
10.1158/0008-5472.can-06-0037
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发表时间：
2006-05-15
期刊：
影响因子：
11.2
通讯作者：
Penn, Linda Z.
中科院分区：
文献类型：
--
作者：
Barsyte-Lovejoy, Dalia;Lau, Suzanne K.;Penn, Linda Z.
Myc癌基因的乘积在癌症中被广泛失调，并用作基因转录的调节剂。尽管受调节基因的广泛特征，但C-MYC的转录靶标对于转化而言至关重要。在这项研究中，我们表明C-MYC显着诱导了H19非编码RNA在各种细胞类型中的表达，包括乳腺上皮，胶质母细胞瘤和成纤维细胞。 C-MYC与印迹控制区域附近的进化保守的电子箱结合，以促进H-19启动子的组蛋白乙酰化和转录启动。此外，c-Myc下调了胰岛素样生长因子2（IGF2）的表达，这是H19/ IGF2基因座的相互烙印基因。我们表明，C-MYC独立调节这两个基因，并不影响H19印迹。实际上，等位基因特异性染色质免疫沉淀和表达分析表明，C-MYC仅结合和驱动母体H19等位基因的表达。 H19在转化中的作用是使用敲低方法来解决的，并表明H19的下调显着降低了乳腺癌和肺癌细胞的克隆发育性和锚固无关的生长。此外，C-MYC和H19表达在原发性乳腺癌和肺癌中表现出很强的关联。这项工作表明H19基因产物的C-MYC诱导在转化中起重要作用。
The product of the MYC oncogene is widely deregulated in cancer and functions as a regulator of gene transcription. Despite an extensive profile of regulated genes, the transcriptional targets of c-Myc essential for transformation remain unclear. In this study, we show that c-Myc significantly induces the expression of the H19 noncoding RNA in diverse cell types, including breast epithelial, glioblastoma, and fibroblast cells. c-Myc binds to evolutionarily conserved E-boxes near the imprinting control region to facilitate histone acetylation and transcriptional initiation of the H-19 promoter. In addition, c-Myc down-regulates the expression of insulin-like growth factor 2 (IGF2), the reciprocally imprinted gene at the H19/ IGF2 locus. We show that c-Myc regulates these two genes independently and does not affect H19 imprinting. Indeed, allele-specific chromatin immunoprecipitation and expression analyses indicate that c-Myc binds and drives the expression of only the maternal H19 allele. The role of H19 in transformation is addressed using a knockdown approach and shows that down-regulation of H19 significantly decreases breast and lung cancer cell clonogenicity and anchorage-independent growth. In addition, c-Myc and H19 expression shows strong association in primary breast and lung carcinomas. This work indicates that c-Myc induction of the H19 gene product holds an important role in transformation.