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  • Taken together our results demonstrate an essential role for


    Taken together, our results demonstrate an essential role for STAT5 in the regulation of adult IESC homeostasis and response to intestinal injury and regeneration. Functionally, genetic activation of Stat5 increases IESC regeneration to replenish injured intestinal epithelia, conferring resistance to intestinal inflammation. Mechanistically, activated STAT5 could repress Bmi1 expression (a quiescent IESC marker). Overall, our work will be beneficial to obtain molecular insights into diseases driven by persistent enteric infection or inflammation.
    Experimental Procedures
    Author Contributions
    Introduction Glioblastoma (GBM) is the most common primary malignant AMG 925 tumor and the median survival of patients is less than 2 years (Brennan et al., 2013). The current standard of therapy involves maximal surgical resection followed by radiotherapy and chemotherapy. However, this treatment strategy fails to eliminate a subset of tumor cells that escape from therapeutic insult and result in tumor recurrence, leading to reduced survival in these patients. A GBM tumor is composed of heterogeneous tumor cell populations that include tumor cells with stem cell properties, termed glioma stem-like cells (GSCs) (Hemmati et al., 2003; Singh et al., 2004). Accumulating evidence indicates that GSCs contribute to radioresistance and subsequent tumor cell repopulation, resulting in recurrent tumors (Bao et al., 2006). Therefore, it is critical to elucidate the molecular mechanisms underlying the radioresistance of GSCs. Maternal embryonic leucine-zipper kinase (MELK) is a serine/threonine kinase and is abundantly expressed in GBM and various other cancers (Gu et al., 2013; Joshi et al., 2013; Minata et al., 2014; Nakano et al., 2008, 2011). We previously reported that MELK is highly expressed in GSCs and its mRNA expression is inversely correlated with the survival of GBM patients (Gu et al., 2013; Nakano et al., 2008). In addition, short hairpin RNA (shRNA)-mediated MELK elimination induces GSC apoptosis with less inhibitory effects on normal neural progenitor cells (NPCs) (Nakano et al., 2005). Mechanistically, MELK associates with two oncogenic transcription factors (c-JUN and FOXM1) in GSCs, but not their normal counterparts, which explains at least in part the cancer-specific, survival-promoting function of MELK (Gu et al., 2013; Joshi et al., 2013). Nonetheless, the pathophysiological roles of MELK in GSC radioresistance remain elusive. Polycomb group (PcG) proteins are important epigenetic regulators of embryonic development and the cell fate decision (Aloia et al., 2013). PcG proteins play a crucial role in mediating global transcriptional repression as two large protein assemblies termed Polycomb repressive complex 1 (PRC1) and PRC2 (Aloia et al., 2013; Margueron and Reinberg, 2011). The core components of PRC2 include EZH2 (enhancer of Zeste homolog 2), Suz12 (suppressor of Zeste 12), and EED (embryonic ectoderm development). In particular, EZH2 functions as a lysine methyltransferase, and EZH2-containing PRC2 catalyzes trimethylation of histone 3 at lysine 27 (H3K27me3) (Margueron and Reinberg, 2011). In a wide range of cancers, including GBM, elevated expression of EZH2 is well recognized and its expression is strongly linked to tumor malignancy and invasiveness (Kim et al., 2013; Radulović et al., 2013). Recent studies, including ours (Kim et al., 2013; Lee et al., 2008), suggested that EZH2 plays a critical role in GSC maintenance and GBM propagation similar to the function of MELK in GSCs. These studies prompted us to speculate that MELK and EZH2 may be involved in the same signaling pathway in GSCs. In this study, we tested the hypothesis that MELK is an upstream regulator of EZH2 signaling to promote GSC survival and resistance to radiation therapy on GBM tumors and GSCs.
    Discussion In this study, we report a number of findings: (1) in GBM tumors, MELK and EZH2 proteins are mostly colocalized in a subset of tumor cells; (2) the fraction of MELK+ and EZH2+ cells preferentially increases in postradio-/chemotherapy recurrent GBM tumors compared with de novo untreated tumors; (3) radioprotection of stem cells by the MELK-EZH2 axis is evolutionarily conserved between C. elegans and human; (4) in human GBM, GSC radioresistance depends largely on MELK-mediated EZH2 signaling in vitro, and MELK knockdown using shRNA radiosensitizes in vivo tumors; (5) EZH2 is a direct target of the oncogenic transcription factor FOXM1 in GSCs; (6) signals derived from the MELK/FOXM1 protein complex are both sufficient and required to drive the transcriptional activity of EZH2 in GSCs; and (7) clinically, MELK, FOXM1, and EZH2 are strongly linked to GBM patient prognosis.