hSETD1A regulates Wnt target genes and controls tumor growth of colorectal cancer cells.
hSETD1A regulates Wnt target genes and controls tumor growth of colorectal cancer cells.
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DOI：
10.1158/0008-5472.can-13-1400
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发表时间：
2014-02-01
期刊：
影响因子：
11.2
通讯作者：
Huang S
中科院分区：
文献类型：
--
作者：
Salz T;Li G;Kaye F;Zhou L;Qiu Y;Huang S
HSETD1A是组蛋白甲基转移酶(HMT)三胸(TrxG)家族的成员，其功能是在活性基因的启动子上甲基化H3K4。尽管混合血统白血病(MLL)家族蛋白调节失调与急性白血病有关，但hSETD1A在癌症中的作用仍不清楚。在这项研究中，我们报告了hSETD1A及其相关的H3K4me3在人类结直肠癌细胞和患者样本中上调。HSETD1A的缺失抑制了结直肠癌细胞的生长、克隆形成和肿瘤的种植。结直肠癌细胞的全基因组表达谱显示，大约50%的Wnt/β-catenin靶基因受hSETD1a基因敲除的影响。我们进一步证明，hSETD1A通过与Wnt信号通路的主要调节因子β-catenin的相互作用，被招募到这些Wnt信号靶基因的启动子。HSETD1AHMT复合体的招募赋予启动子相关的H3K4me3，从而导致转录预起始复合体的组装和转录激活。此外，hSETD1a的表达水平与H3K4me3在Wnt/β-catenin靶基因启动子上的丰富以及这些基因在结直肠癌中的异常激活正相关。这些结果为hSETD1a和β-catenin在调控Wnt靶基因以及在体外和体内结直肠癌细胞生长中的协同作用提供了新的生物学和机制方面的见解。
hSETD1A is a member of the trithorax (TrxG) family of histone methyltransferases (HMT) that methylate H3K4 at promoters of active genes. Although misregulation of mixed lineage leukemia (MLL) family proteins has been associated with acute leukemia, the role of hSETD1A in cancer remains unknown. In this study, we report that hSETD1A and its associated H3K4me3 are upregulated in human colorectal cancer cells and patient samples. Depletion of hSETD1A inhibits colorectal cancer cell growth, colony formation, and tumor engraftment. Genome-wide expression profiling of colorectal cancer cells reveals that approximately 50% of Wnt/β-catenin target genes are affected by the hSETD1A knockdown. We further demonstrate that hSETD1A is recruited to promoters of those Wnt signaling target genes through its interaction with β-catenin, a master regulator of the Wnt signaling pathway. The recruitment of the hSETD1A HMT complex confers promoter-associated H3K4me3 that leads to assembly of transcription preinitiation complex and transcriptional activation. Furthermore, the expression levels of hSETD1A are positively correlated with H3K4me3 enrichment at the promoters of Wnt/β-catenin target genes and the aberrant activation of these genes in human colorectal cancer. These results provide new biologic and mechanistic insights into the cooperative role of hSETD1A and β-catenin in regulation of Wnt target genes as well as in colorectal cancer cell growth in vitro and in vivo.