Hypermethylation reduces expression of tumor‐suppressor PLZF and regulates proliferation and apoptosis in non‐small‐cell lung cancers

Deregulation of promyelocytic leukemia zinc finger protein (PLZF), a tumor suppressor gene, was reported in different types of solid tumors. This study for the first time explored the reduced expression of PLZF and its effects in non‐small‐cell lung cancer (NSCLC) carcinogenesis. PLZF was found to be downregulated by 62.8% in 87.1% of 154 paired NSCLC samples by quantitative real‐time PCR, and its expression was found to be associated with the sex of the patient ( P =0.02). Further analysis showed that down‐regulation of PLZF in 35.6% NSCLC samples (31 out of 87) was triggered by hypermethylation in the promoter region. This was validated by demethylation analysis using the A549 cell line. Dual‐luciferase reporter assay indicated that CTCF binding to the promoter region could activate PLZF transcription. Overexpression of PLZF in both A549 and LTEP lung cancer cell lines was found to inhibit proliferation and increase apoptosis. Therefore, reduced expression of PLZF was found to be common in NSCLC. PLZF down‐regulation was partially correlated with hypermethylation in the promoter region. Decreased levels of PLZF expression may contribute to the pathogenesis of NSCLC by promoting cell survival. Therefore, the restoration of PLZF expression may serve as a new strategy for NSCLC therapy.—Wang, X., Wang, L., Guo, S., Bao, Y., Ma, Y., Yan, F., Xu, K., Xu, Z., Jin, L., Lu, D., Xu, J., Wang, J.‐C. Hypermethylation reduces expression of tumor‐suppressor PLZF and regulates proliferation and apoptosis in non‐small‐cell lung cancers. FASEBJ. 27, 4194‐4203 (2013). www.fasebj.org