N-terminal truncated carboxypeptidase E represses E-cadherin expression in lung cancer by stabilizing the Snail-HDAC complex.

ABSTRACT: The N-terminal truncated carboxypeptidase E (CPE?N) protein, an alternative splicing product of the carboxypeptidase E gene, has recently been recognized as an independent predictor for the recurrence and metastasis of lung adenocarcinoma. In this study, we showed that CPE?N may accelerate lung cancer invasion via an E-cadherin-dependent mechanism. In vitro experiments and in vivo bioluminescence imaging assay revealed CPE?N promoted the mobility and invasion of human lung cancer cells by suppressing endogenous expression of E-cadherin, a critical regulator for epithelial tissue homeostasis. Further mechanistic analyses revealed that CPE?N directly interacted with and stabilized the Snail/HDAC1/HDAC3 complex within the promoter region of the E-cadherin-encoding CDH1 gene. CPE?N overexpression led to a reduction of histone H3K9 acetylation and an increase of H3K9 and H3K27 trimethylation in the CHD1 gene promoter and ultimately inhibited E-cadherin transcription. In addition, correlations among CPE?N, E-cadherin expression and tumor progression in 195 cases of lung adenocarcinoma patients were analyzed. Higher nuclear expression of CPE?N was detected in patients with advanced stage of lung adenocarcinoma. Nuclear expression of CPE?N was negatively correlated with the cell membrane expression of E-cadherin. Collectively, our findings illustrated that CPE?N was involved in the transcriptional regulation of the epithelial-mesenchymal transition-related gene CDH1 and provide novel insights into CPE?N-associated lung cancer metastasis.

SUBMITTER: Sun J 

PROVIDER: S-EPMC7136916 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature