Genome wide binding and transcriptome analyses demonstrate t

Genome-wide binding and transcriptome analyses demonstrate that Fbxl10 directly binds the Areg, Mdk, Lmnb1, Thbs1, Mgp and Cxcl12 locus and thereby might influences the expression of these migration associated genes. The expression of epidermal growth factor (EGF)-like molecule Amphiregulin (Areg) is enhanced by Fbxl10. Through EGFR binding AREG activates major intracellular signalling cascades controlling cell survival, proliferation and motility thereby fulfil emerging functions in orchestrating tissue repair, immunity and inflammation [30]. MDK (midkine, also called Amphiregulin-associated protein) promotes the growth, survival and migration of various cells, and plays important roles in epithelial mesenchymal interactions and organogenesis [31]. In humans, identification of MDK in serum and tissues is usually associated with diseases, including inflammation and cancers [32], [33], [34], [35]. MDK initiates downstream signalling systems such as Src family kinases and tyrosine phosphorylation [35]. However, the upstream signalling that leads to MDK accumulation remains elusive. Here, we showed that Fbxl10 binding to the Mdk gene leads to up-regulation of Mdk expression. In addition, enhanced expression of B-type lamin Lmnb1 was found after Fbxl10 binding. A- and B-type lamins form the nuclear lamina scaffold adjacent to the inner nuclear membrane. B-type lamins confer elasticity and lamins also contributed to orthopoxvirus variola regulation and various signalling pathways affecting gene expression [36], [37], [38], [39], [40]. Recent findings suggest a highly cross-linked and interdependent regulation of these different functions [41]. Aside from their role as structural elements, fibroblasts are the key sites of chemokine synthesis, which initiates a cascade of events involved in wound healing and clearance of invading microorganisms. Consistent with our previous work, showing that Fbxl10 binds directly to and demethylates histones of the Ccl7 promoter in a gene locus-specific manner, here we could show that Fbxl 10 regulates several chemokines like Ccl2, Ccl7, Ccl17, Ccl9 and the C-C chemokine receptor type 5 (Ccr5) [18]. FBXL10 overexpression is widely seen in patients with human tumors like acute myeloid leukemia, breast, seminoma and pancreatic ductal adenocarcinoma [7], [8], [9], [42]. Given all of this evidence and the fact that formation of metastases requires active tumor cell migration and invasion, selective inhibition of FBXL10 may be a potential therapeutic strategy to achieve improvement in these diseases. This question will be addressed in future studies.
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Acknowledgments
Introduction Hypoxia plays a critical role in tumor angiogenesis, apoptotic resistance, metabolic switch from oxidation to glycolysis, and genomic instability, thereby contributing to cancer development [1], [2]. Hypoxia is evident in prostate tumors, increasing with clinical stage, patient age, and is associated with a lower biochemical free relapse rate [3], [4], [5]. Moreover, it has been suggested that radiotherapy-resistant hypoxic tumor cells govern the overall responsiveness of prostate cancer to current therapies [3]. Crosstalk between hypoxia and androgen receptor (AR) signaling via the key transcription factors hypoxia-inducible factor 1-alpha (HIF1α) and hypoxia-inducible factor 2-alpha (HIF2α; also known as EPAS1) [6] has been extensively studied: Androgens induce HIF1α activation through the PI3K/AKT pathway [7]; hypoxia and AR synergistically regulate the expression of prostate-specific antigen (PSA) [8], [9]; hypoxia enhances the transcriptional activity of AR at low androgen level and contributes to androgen-independent growth of LNCaP cells [10]. Additionally, HIF1α can form a ternary complex with AR and β-catenin at the androgen response elements (AREs) of AR target genes [11]. Consistent with these findings, synergistic targeting of AR and HIF1α has been shown to inhibit castration-resistant prostate cancer (CRPC) cells [9].