In summary we elucidated the
In summary, we elucidated the in vitro activities of KDM1B in regulation of PC cell proliferation and apoptosis. These studies provided a novel insight into the previously unrecognized roles of KDM1B in human PC cells. We showed for the first time that KDM1B knockdown attenuated proliferation and induced apoptosis of PC cells. In the future, better understanding of epigenetic downstream target genes and pathways controlled by KDM1B would aid in developing novel small molecule inhibitors which might confer selective effects against PC.
Conflicts of interest
Acknowledgements This work was supported by the National Natural Science Foundation of China (81402186) and Shaanxi provincial social development project (2016SF-183).
Introduction The effectiveness of systemic cancer therapy is limited by the inevitable emergence of drug resistance. A diverse range of molecular mechanisms are implicated in the reduced treatment responses . EMT is a process in which an epithelial cell, characterized by apical-basal polarity and interaction with a basement membrane, undergoes a shift towards a more motile, invasive state. For a long time, EMT was considered the driving mechanism of the epithelial cancer cell to spread to distant organs and formation of metastatic colonies. This paradigm was very recently challenged by the finding that AH 7614 can metastasize also without undergoing EMT , . In the same studies the important role of the EMT program in drug resistance was confirmed. The (partial) activation of either the epithelial or the mesenchymal program is largely dependent on the contextual signals that reach the cell from its microenvironment (inflammation, hypoxia, metabolic stress etc.). TGF-β1, an inflammatory cytokine mainly produced by macrophages and myofibroblasts, is the most studied inducer of the mesenchymal phenotype , , . Hypoxia has also been reported to induce EMT in cancer cells , . Furthermore, numerous studies have shown that cell lines derived from various epithelial cancers undergo mesenchymal differentiation in vitro when made resistant to conventional chemotherapy , ,  as well as to targeted agents , , . In response to stress such as nutrient deprivation, severe hypoxia or pH changes, the tumor cell will also engage additional signaling pathways such as the unfolded protein response (UPR) , ). The UPR is activated when the stressor disrupts normal protein folding in the endoplasmic reticulum (ER) with the aim to ensure survival of the cell. However, when cell stress is too severe and prolonged, the UPR will facilitate apoptosis . One of the main UPR signaling pathways is driven by protein kinase RNA-like endoplasmic reticulum kinase (PERK) activation, an ER transmembrane kinase, which will lead to inhibition of Eukaryotic Initiation Factor 2a (eIF2a) by phosphorylation hereby subsequently inducing the Activating Transcription Factor 4 (ATF4) transcriptional program. Deactivation of eIF2a will silence global mRNA translation to reduce the ER protein load . ATF4 is generally regarded as a pro-survival regulator involved in drug resistance and its expression correlates with EMT , . Acriflavine (ACF) is a heteroaromatic dye with antibacterial and antiviral effects . More recently, its potential as an anticancer agent emerged as acriflavine has topo-isomerase inhibitor activity . It also blocks the HIF pathway, an important driver of cancer aggressiveness, by preventing the dimerization of the HIF-1 subunits, HIF-1α and HIF-1β . Furthermore, there are also reports that show a close link between HIF signaling, EMT and cancer aggressiveness , , , . In this study, we show that acriflavine inhibits epithelial-to-mesenchymal transition induced by TGF-β1 or CoCl2 (model of severe hypoxia) and in a model of acquired drug resistance. Furthermore, acriflavine blocks UPR via inhibition of the ATF4 transcriptional program and resensitizes drug resistant cells. These characteristics encourage further studies to repurpose ACF for systemic cancer therapy.