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 (CPEΔN) 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 CPEΔN may accelerate lung cancer invasion via an E-cadherin-dependent mechanism. <i>In vitro</i> experiments and <i>in vivo</i> bioluminescence imaging assay revealed CPEΔN 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 CPEΔN directly interacted with and stabilized the Snail/HDAC1/HDAC3 complex within the promoter region of the E-cadherin-encoding <i>CDH1</i> gene. CPEΔN overexpression led to a reduction of histone H3K9 acetylation and an increase of H3K9 and H3K27 trimethylation in the <i>CHD1</i> gene promoter and ultimately inhibited E-cadherin transcription. In addition, correlations among CPEΔN, E-cadherin expression and tumor progression in 195 cases of lung adenocarcinoma patients were analyzed. Higher nuclear expression of CPEΔN was detected in patients with advanced stage of lung adenocarcinoma. Nuclear expression of CPEΔN was negatively correlated with the cell membrane expression of E-cadherin. Collectively, our findings illustrated that CPEΔN was involved in the transcriptional regulation of the epithelial-mesenchymal transition-related gene <i>CDH1</i> and provide novel insights into CPEΔN-associated lung cancer metastasis.