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A nucleus-targeting peptide antagonist towards EZH2 displays therapeutic efficacy for lung cancer. | LitMetric
EZH2 is an overexpressed nuclear protein associated with relatively poor survival and chemoresistance in lung cancer. In this study, a nucleus-targeting peptide antagonist EIP103 capable of penetrating cell membrane and nuclear envelope was identified, and has high binding affinity towards EZH2 localized in the nucleus of lung cancer cells. To improve the stability and therapeutic efficacy of EIP103, PEG-PE micelle encapsulated EIP103 (M-EIP103) was successfully conducted. In vitro results indicated that M-EIP103 exhibited better stability, higher intracellular uptake and stronger cytotoxicity than free EIP103 in H446 and A549 cells. Mechanistic studies suggested that M-EIP103 inhibited proliferation by down-regulating the H3K27me3 expression level in cancer cells. In vivo assays further confirmed that both EIP103 and M-EIP103 significantly inhibited lung cancer progression. Notably, enhanced therapeutic efficacy of EIP103 by PEG-PE micelle encapsulation could be identified. The observed anti-tumor activity of EIP103 and M-EIP103 demonstrated a promising therapy to improve clinical treatment of lung cancers as well as other EZH2-overexpressing malignant cancers. This study also illustrates the feasibility of developing targeted delivery of therapeutic peptides to nucleus for cancer therapy.
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