A large body of literature have reported that various cellul

A large body of literature have reported that various cellular pathways are dysregulated in NPC [19]. Among these pathways, Akt is frequently hyperactivated in NPC and regulates diverse cellular processes including tumor cell growth, proliferation, metabolism, survival and invasion, as well as angiogenesis [20]. Many oncoproteins and tumor suppressors are regulated by Akt signaling pathway through activating or inactivating mechanisms, respectively [20]. Thereby, Akt is considered as key regulator of tumorigenesis and tumor aggressiveness. Molecularly targeting components of the Akt pathway has been proven to be potential utility for cancer therapy and prevention [20]. Our results demonstrated that eudesmin significantly suppressed the activation of Akt signaling pathway in NPC cells. Moreover, we found that inhibition of Akt signaling pathway reduced the BIX 02565 synthesis of EZH2 in NPC cells. Knockdown of EZH2 by siRNA attenuated the effects of Akt overexpression on cell viability and apoptosis. It could be inferred that eudesmin exerted its antitumor activity via down-regulating EZH2 expression through inhibiting Akt signaling pathway.
Conclusion
Disclosure statement
Declaration of interests
Significance
Introduction In recent years, many studies have revealed dysregulation of polycomb repressive complex 2 (PRC2) in cancer. PRC2 epigenetically suppresses gene transcription through tri-methylation of lysine 27 in histone 3 (H3K27me3). Among others, the catalytic capacity of PRC2 can be potentiated by either overexpression or gain-of-function (GoF) mutations (e.g., Y646F and Y646N) of the enhancer of zeste homolog 2 gene (EZH2), which encodes the methyltransferase unit of PRC2 (Kim and Roberts, 2016). Recent attempts to decipher the significance of elevated PRC2 activity for tumorigenesis have revealed tissue-specific expression of wild-type (WT) Ezh2 to foster breast, prostate, and lung epithelial neoplasia in mice (Koppens et al., 2017, Li et al., 2009, Zhang et al., 2016). Expression of Ezh2Y646F or Ezh2Y646N in murine B cells likewise drove hyperplastic transformation ultimately progressing into lymphoma (Béguelin et al., 2013, Berg et al., 2014, Souroullas et al., 2016). Moreover, in conjunction with BrafV600E, substitution of the endogenous Ezh2 with Ezh2Y646F led to emergence of non-metastatic melanocytic tumors (Souroullas et al., 2016). In an autochthonous mouse model of malignant melanomagenesis, homozygous deletion of Ezh2 abolished cutaneous melanoma initiation and metastatic spread (Zingg et al., 2015). However, it remains unresolved whether a gain in EZH2 activity is sufficient to drive malignant metastatic melanoma. In solid cancers, together with cutaneous melanoma, PRC2 activity has been connected to regulation of cell proliferation and tumor growth through repression of tumor suppressors, such as CDKN1A and CDKN2A (Kim and Roberts, 2016). In the context of oncogenic NRASQ61K signaling and Cdkn2a gene knockout, mice spontaneously develop melanoma (Ackermann et al., 2005). Yet, in these animals, Ezh2 ablation is sufficient to prevent tumor growth (Zingg et al., 2015). Hence, EZH2 might contribute to melanomagenesis by controlling genes beyond traditional tumor suppressors.
Results
Discussion Recent publications have revealed that a large set of solid cancers exhibit loss of primary cilia (Cao and Zhong, 2016), in line with reduced ciliary gene expression (Shpak et al., 2014). However, the mechanisms by which cancer cells lose their cilia and the significance of cilia loss for tumorigenesis have remained elusive. Our study reveals how assembly and disassembly of the primary cilium are epigenetically regulated by PRC2. In particular, we identify the PRC2 component EZH2 to promote tumorigenesis by suppressing primary cilium genes, which results in deciliation. Ciliary deconstruction in turn initiates the formation of metastasizing melanoma by promoting WNT/β-catenin signaling. Thus, the primary cilium functions as a tumor suppressor organelle of malignant metastatic melanoma.