Methylation-mediated silencing of the LIM homeobox 6 (LHX6) gene promotes cell proliferation in human pancreatic cancer
Methylation-mediated silencing of the LIM homeobox 6 (LHX6) gene promotes cell proliferation in human pancreatic cancer
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DOI：
10.1016/j.bbrc.2020.03.120
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发表时间：
2020-06-04
影响因子：
3.1
通讯作者：
Fukushige, Shinichi
中科院分区：
文献类型：
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作者：
Abudurexiti, Yakefujiang;Gu, Zhaodi;Fukushige, Shinichi
通过异常DNA甲基化引起的表观遗传基因沉默导致肿瘤发生中关键细胞通路的丢失。使用甲基-CpG靶向转录激活（Meta）方法搜索胰腺癌中DNA甲基化介导的沉默基因，并选择参与胚胎发生和头部发育的转录因子LHX 6（LIM同源框6）作为强候选基因。LHX 6在大多数胰腺癌细胞系中下调（83%，10/12），主要通过启动子高甲基化和组蛋白去乙酰化。此外，LHX 6在原发性胰腺癌标本中以肿瘤特异性方式甲基化（57%，16/28）。LHX 6的再表达抑制LHX 6低表达胰腺癌细胞系PK-1和PK-9中的集落形成和增殖。相比之下，LHX 6的敲低加速了LHX 6高表达胰腺癌细胞系PCI-35和MIA PaCa-2中的细胞增殖。为了分析LHX 6下游基因，我们使用LHX 6诱导型PK-1和PK-9进行了微阵列分析，发现LHX 6诱导上调了几个具有肿瘤抑制功能的基因。其中，我们集中在TFPI 2（组织因子途径抑制剂-2），并发现TFPI 2在所有12个胰腺癌细胞系中显著下调。我们目前的研究结果表明，LHX 6的表观遗传失活在胰腺肿瘤的发生中起着重要的作用，通过促进细胞增殖，通过异常转录调控的几个癌症相关基因。(C)2020爱思唯尔公司All rights reserved.
Epigenetic gene silencing by aberrant DNA methylation leads to loss of key cellular pathways in tumorigenesis. DNA methylation-mediated silenced genes in pancreatic cancer were searched for using the methyl-CpG targeted transcriptional activation (MeTA) method, and LHX6 (LIM homeobox 6), a transcription factor involved in embryogenesis and head development, was selected as a strong candidate gene. LHX6 was downregulated in most of the pancreatic cancer cell lines (83%, 10/12), mainly through promoter hypermethylation and histone deacetylation. Furthermore, LHX6 was methylated in primary pancreatic cancer specimens (57%, 16/28) in a tumor-specific manner. Re-expression of LHX6 inhibited colony formation and proliferation in LHX6 low-expressing pancreatic cancer cell lines, PK-1 and PK-9. In contrast, knockdown of LHX6 accelerated cell proliferation in LHX6 high-expressing pancreatic cancer cell lines, PCI-35 and MIA PaCa-2. In order to analyze LHX6 downstream genes, we performed microarray analyses using LHX6 inducible PK-1 and PK-9 and found that LHX6 induction upregulated several genes that had tumor suppressive functions. Among these, we focused on TFPI2 (Tissue factor pathway inhibitor-2) and found that TFPI2 was greatly downregulated in all twelve pancreatic cancer cell lines. Our present results suggest that epigenetic inactivation of LHX6 plays an important role in pancreatic tumorigenesis by promoting cell proliferation through aberrant transcriptional regulation of several cancer-related genes. (C) 2020 Elsevier Inc. All rights reserved.