Encoded by the gene PARK2, Parkin, an E3 ubiquitin ligase, is a key regulator in mitophagy and closelyassociated with Parkinson's disease (PD). Recently, Parkin has emerged as a critical tumor suppressor gene in various cancers, including lung cancer. The expression of Parkin is commonly observed to be downregulated in cancer, and one of the underlying mechanisms is via epigenetic modifications, such as DNA methylation and histone modifications in the context of tumorigenesis. Since the mutation rate of Parkin is low in non-small cell lung cancer (NSCLC), we investigated whether Parkin’s expression is downregulated by epigenetic regulatory mechanisms. We first observed that treatment with FDA-approved epigenetic modification drugs DNA methyltransferase (DNMT) inhibitor azacytidine and the pan-histone deacetylase (HDAC) inhibitors vorinostat (SAHA) increased PARK2 gene expression and retarded lung cancer cell growth. Next, through chromatin immunoprecipitation (ChIP) and bisulfide sequencing, we obtained results on potential target proteins that exhibit direct effects on PARK2 expression. Lastly, we investigated the combinational effect of the epigenetic drugs with cancer chemotherapeutic agents both in vivo and in vitro and found that up-regulation of Parkin expression enhances the therapeutic efficacy of cancer chemotherapeutic agents. In summary, elucidating the underlying epigenetic regulation of Parkin extends our knowledge on Parkin and its implication in mitophagy, PD and cancer.