HDAC1 promotes lung adenocarcinoma progression via the nuclear accumulation of β-catenin

Abstract

Histone deacetylase 1 (HDAC1) is frequently dysregulated in various human malignancies; however, the molecular mechanisms underlying its role in non-small cell lung cancer (NSCLC) remain unclear. HDAC1 expression was evaluated in 157 paired lung adenocarcinoma (LUAD) and adjacent non-neoplastic tissues using tissue microarray and immunohistochemical analysis. The functional role of HDAC1 was assessed in A549, H1299 and H1975 NSCLC cells following stable knockdown or overexpression, using Cell Counting Kit-8, colony formation and Transwell assays. Downstream signaling was examined by western blotting and nuclear-cytoplasmic fractionation. Rescue experiments were performed by overexpressing β-catenin in HDAC1-knockdown cells and the findings were further validated in a subcutaneous xenograft tumor model in nude mice. HDAC1 was markedly upregulated in LUAD tissues and associated with lymph node metastasis and poor differentiation. Functionally, HDAC1 knockdown inhibited proliferation, colony formation, migration and invasion in all three NSCLC cell lines. These effects were accompanied by downregulation of c-Myc, cyclin D1 and vimentin, upregulation of E-cadherin and reduced nuclear β-catenin accumulation. Conversely, HDAC1 overexpression enhanced malignant phenotypes and promoted β-catenin nuclear accumulation. Notably, the phosphorylation of AKT (Thr308 and Ser473) and ERK1/2 remained unaltered following HDAC1 modulation. β-catenin overexpression effectively eliminated the tumor-suppressive effects of HDAC1 knockdown both in vitro and in vivo. These findings indicated that HDAC1 is a critical promoter of LUAD progression, acting at least in part through β-catenin nuclear accumulation. This provided a mechanistic rationale for targeting the HDAC1/β-catenin axis as a potential epigenetic therapeutic strategy in LUAD.