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  • In conclusion our findings demonstrated

    2019-11-26

    In conclusion, our findings demonstrated that S1PC augments HMOX1 expression in a NO-dependent manner, and its effects are associated with the enhancement of BACH1 degradation. In addition, S1PC and NO potentially degrade BACH1 based on the observation that nuclear degradation of BACH1 differs from what was observed in previous studies [22,33,35]. Although the mechanism by which S1PC interacts with NO remains unclear, the inhibition of BACH1 expression by S1PC provides novel insight into potential therapeutic strategies for the treatment of various inflammatory diseases.
    Conflicts of interest
    Acknowledgments
    Introduction Pancreatic cancer (PC) is one of the common malignant tumors in digestive tract with a high fatality rate, which is difficult to diagnose and treat [1]. The operative mortality is high and the prognosis is extremely poor because of the high recurrence rate [2,3]. Therefore, an increasing understanding of the complex molecular basis of PC and exploring novel therapeutic targets may contribute to the clinical treatment of this aggressive malignancy. In the recent years, more and more evidence support that dysregulated epigenetic regulatory processes play a central role in cancer onset and progression [[4], [5], [6]]. Reversible histone methylation is an important process within epigenetic regulation, and the investigations of its role in cancer have led to the identification of lysine methyltransferases and demethylases as promising targets for cancer therapy [[7], [8], [9]]. Histone demethylases (KDMs) are a family of enzymes that catalyze the removal of methyl groups not only from histones but other proteins as well, playing a pivotal role in dynamic regulation of numerous vx 765 mg functions such as gene transcription, chromatin stability, DNA replication and repair [[10], [11], [12]]. The first histone demethylase to be discovered was lysine-specific demethylase 1 (LSD1), which are homologues of the flavin-containing amine oxidases [13,14]. Further researches identified an additional family of histone demethylases, which can be divided into five subfamilies (KDM2/7, KDM3, KDM4, KDM5, and KDM6 subfamilies), belonging to the Fe2+ and α-ketoglutarate-dependent Jumonji C-terminal domain family (JMJD) [[15], [16], [17]]. As a deeper understanding of their involvement in transcriptional regulation is gained, KDMs are becoming increasingly interesting targets for drug development. KDM1 family includes KDM1 A (LSD1) and KDM1B (LSD2), which scores an overall 33% identity in the SWIRM domain, the FAD coenzyme-binding motif and the C-terminal amine oxidase domains [13,18]. In contrast to LSD1, LSD2 lacks the “tower domain”, which is instrumental to the tight LSD1-CoREST association [[18], [19], [20]]. However, LSD2 possesses a zinc finger domain in the N-terminal region, which may confer biochemical and biological properties distinct from those of LSD1. KDM1 A is involved in a wide array of biological processes including cell proliferation, chromosome segregation and embryonic development. Recently, KDM1 A has been identified as a potential target for cancer therapeutics. Although KDM1B shares similar substrate specificity with KDM1 A, it is evident that instead of functioning as a transcriptional repressor, KDM1B is important for transcriptional elongation factors and phosphorylated RNA polymerase II [21,22]. KDM1B tends to associates predominantly with the gene bodies of actively transcribed genes, but does not assemble the promoter as KDM1 A [20]. These findings suggest that KDM1 A and KDM1B likely interact with different protein domain and show quite distinct genomic distribution profiles. According to the discoveries from the high-throughput sequencing projects of primary human tumor samples, mRNA expression levels of both KDM1 A and KDM1B were greatly increased in several different types of tumors, including multiple myeloma, esophageal squamous cell carcinomas, renal cell carcinomas, breast and colorectal cancer and glioblastoma [23,24]. KDM1B has been linked to numerous important biological function including genomic imprinting, transcription regulation, regulation of somatic cell reprogramming, DNA methyltransferases and growth factor signaling [[25], [26], [27], [28]]. However, it is still not clear whether KDM1B is also involved in the development of PC.