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Methylation-mediated silencing of the LIM homeobox 6 (LHX6) gene promotes cell proliferation in human pancreatic cancer.

Abstract：

: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.

journal_name

Biochem Biophys Res Commun

journal_title

Biochemical and biophysical research communications

authors

Abudurexiti Y,Gu Z,Chakma K,Hata T,Motoi F,Unno M,Horii A,Fukushige S

doi

10.1016/j.bbrc.2020.03.120

subject

Has Abstract

pub_date

2020-06-04 00:00:00

pages

626-632

issue

3

eissn

0006-291X

issn

1090-2104

pii

S0006-291X(20)30611-2

journal_volume

526

pub_type

杂志文章

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