KMT2A histone methyltransferase contributes to colorectal cancer development by promoting cathepsin Z transcriptional activation
KMT2A histone methyltransferase contributes to colorectal cancer development by promoting cathepsin Z transcriptional activation
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KMT2A 组蛋白甲基转移酶通过促进组织蛋白酶 Z 转录激活促进结直肠癌的发生
DOI：
10.1002/cam4.2226
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发表时间：
2019-07-01
期刊：
影响因子：
4
通讯作者：
Ye, Le-chi
中科院分区：
文献类型：
--
作者：
Fang, Yang;Zhang, Dan;Ye, Le-chi
越来越多的证据支持表观遗传修饰因子在癌症发生过程中是异常的，并且在癌症进展中起着重要作用。在这些异常的表观遗传修饰因子中，组蛋白甲基转移酶KMT2A在体细胞肿瘤中的功能尚不清楚。通过分析患者组织中KMT2A的表达，我们发现与邻近正常组织相比，KMT2A在结直肠癌组织中过表达，其表达与癌症分期呈正相关。在KMT2A‐敲低HCT116和DLD1细胞中，细胞的侵袭和迁移因此受到抑制。此外，KMT2A缺失在体内有效抑制肿瘤转移。从机制上讲，组织蛋白酶Z （CTSZ）被证明是KMT2A重要的下游基因。进一步的研究表明，p65可以在下游基因CTSZ的启动子区域募集KMT2A， p65的敲低可以减少CTSZ启动子上的KMT2A。最后，我们的研究揭示了KMT2A通过靶向CTSZ在表观遗传学上促进癌症进展，CTSZ在癌症侵袭和转移中具有特异性功能。
Accumulating evidence supports the notion that epigenetic modifiers are abnormal in carcinogenesis and have a fundamental role in cancer progression. Among these aberrant epigenetic modifiers, the function of histone methyltransferase KMT2A in somatic tumors is not well known. By analyzing KMT2A expression in patient tissues, we demonstrated that KMT2A was overexpressed in colorectal cancer tissues in comparison with adjacent normal tissues and its expression was positively correlated with cancer stages. In KMT2A‐knockdown HCT116 and DLD1 cells, cell invasion and migration were consequently suppressed. In addition, KMT2A depletion effectively suppressed cancer metastasis in vivo. Mechanistically, cathepsin Z (CTSZ) was demonstrated to be an important downstream gene of KMT2A. Further studies showed that p65 could recruit KMT2A on the promoter region of the downstream gene CTSZ and knockdown of p65 could reduce the KMT2A on the promoter of CTSZ. Finally, our present study revealed that KMT2A epigenetically promotes cancer progression by targeting CTSZ, which has specific functions in cancer invasion and metastasis.