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Intrinsic and/or acquired resistance of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) commonly occurs in patients with non-small-cell lung cancer (NSCLC). Here, we developed a combined therapy of histone deacetylase inhibition by a novel HDAC inhibitor, YF454A, with erlotinib to overcome EGFR-TKI resistance in NSCLC. EXPERIMENTAL APPROACHThe sensitization of the effects of erlotinib by YF454A was examined in a panel of EGFR-TKI-resistant NSCLC cell lines in vitro and two different erlotinib-resistant NSCLC xenograft mouse models in vivo. Western blotting and Affymetrix GeneChip expression analysis were further performed to determine the underlying mechanisms for the effects of the combination of erlotinib and YF454A. KEY RESULTSYF454A and erlotinib showed a strong synergy in the suppression of cell growth by blocking the cell cycle and triggering cell apoptosis in EGFR-TKI-resistant NSCLC cells. The combined treatment led to a significant decrease in tumour growth and tumour weight compared with single agents alone. Mechanistically, this combination therapy dramatically down-regulated the expression of several crucial EGFR-TKI resistance-related receptor tyrosine kinases, such as Her2, c-Met, IGF1R and AXL, at both the transcriptional and protein levels and consequently blocked the activation of downstream molecules Akt and ERK. Transcriptomic profiling analysis further revealed that YF454A and erlotinib synergistically suppressed the cell cycle pathway and decreased the transcription of cell-cycle related genes, such as MSH6 and MCM7. CONCLUSION AND IMPLICATIONSOur preclinical study of YF454A provides a rationale for combining erlotinib with a histone deacetylase inhibitor to treat NSCLC with EGFR-TKI resistance.Abbreviations CI, combination index; EGFR, epidermal growth factor receptor; HDAC, histone deacetylase; NSCLC, non-small-cell lung cancer; TKIs, tyrosine kinase inhibitors

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Albino became a novel kind of tea cultivar in China recently. In this study, transcriptome and whole-genome bisulfite sequencing (WGBS) were employed to investigate the shading effects on leaf color conversion and biosynthesis of three major secondary metabolites in the albino tea cultivar “Yujinxiang”. The increased leaf chlorophyll level was likely the major cause for shaded leaf greening from young pale or yellow leaf. In comparison with the control, the total catechin level of the shading group was significantly decreased and the abundance of caffeine was markedly increased, while the theanine level was nearly not influenced. Meanwhile, differentially expressed genes (DEGs) enriched in some biological processes and pathways were identified by transcriptome analysis. Furthermore, whole-genome DNA methylation analysis revealed that the global genomic DNA methylation patterns of the shading period were remarkably altered in comparison with the control. In addition, differentially methylated regions (DMRs) and the DMR-related DEG analysis indicated that the DMR-related DEGs were the critical participants in biosynthesis of the major secondary metabolites. These findings suggest that DNA methylation is probably responsible for changes in the contents of the major secondary metabolites in Yujinxiang.