The role of androgen and androgen receptor (AR) in breast carcinogenesis has long been a disputed issue. This report provides a mechanistic insight into how androgen and AR contributes to invasion and metastasis of breast cancer. We find that dihydrotestosterone (DHT) is able to induce the epithelial-to-mesenchymal transition in breast cancer cells in an AR-dependent/estrogen receptor-independent manner. This process is dependent on the demethylation activity of lysine-specific demethylase 1A (LSD1) by epigenetically regulating the target genes E-cadherin and vimentin. In vivo, DHT promotes metastasis in a nude mouse model, and AR and LSD1 are indispensable in this process. We establish that higher expression of nucleus AR to cytoplasm AR associated with worse prognostic outcomes in breast cancer patient samples. This study maps an 'androgen-AR/LSD1-target genes' pathway in breast carcinogenesis, implicating the importance of hormonal balance in women, and the potential clinical significance of serum androgen and AR in prediction of breast cancer and selection of breast cancer therapy.
Primary human fibroblasts undergoing oncogene-induced or replicative senescence are known to form senescence-associated heterochromatin foci (SAHF), which can stabilize the state of senescence. The retinoblastoma (RB) protein has an important role in SAHF; cells that lack active RB pathway fail to form SAHF. It has been known that the posttranslational modifications of RB, for example, phosphorylation, regulate its function. To date, whether methylation of RB impacts on the SAHF formation is unknown. Here we report that JMJD3, a histone demethylase catalyzing the tri-methylation of H3K27 (H3K27me3), can demethylate the nonhistone protein RB at the lysine810 residue (K810), which is a target of the methyltransferase Set7/9. We detected a significant upregulation of JMJD3 during cellular senescence and SAHF formation in WI38 cells induced by H-RasV 12 , and we found that ectopic expression of JMJD3 promoted cellular senescence and SAHF formation in WI38 cells. Furthermore, during the process of SAHF assembly, JMJD3 was transported to the cytoplasm and interacted with RB through its demethylase domain JmjC. Significantly, our data demonstrated that the JMJD3-mediated demethylation of RB at K810 impeded the interaction of RB with the protein kinase CDK4 and resulted in reduced level of phosphorylation of RB at Serine807/811 (S807/811), implicating an important role of the interplay between the demethylation and phosphorylation of RB in SAHF assembly. This study highlights the role of JMJD3 as a novel inducer of SAHF formation through demethylating RB and provides new insights into the mechanisms of cellular senescence and SAHF assembly. Cellular senescence is an irreversible process of cell cycle arrest. The senescent cells remain metabolically active but are unable to express genes required for cell proliferation. 1,2 The known causes of cellular senescence include telomere shortening, oxidative stress, DNA damage and hyperoncogenic signaling. 3 H-RasV 12 has been used as a model to induce senescence in normal cells. [4][5][6] Senescent cells are typically characterized by a large flat morphology and the expression of a senescence-associated β-galactosidase activity (SA-β-gal), and nuclei of senescence cells may remodel to form the heterochromatin structures termed the senescenceassociated heterochromatin foci (SAHF). 7 SAHF are condensed regions of DNA that correlate with transcriptionally inactive sites. 8 These heterochromatin foci are hallmarked by H3K9me3 and the incorporation of heterochromatin protein HP1, macroH2A, PML (promyelocy leukemia protein) and HMGA1 (high mobility group AT-hook 1). 7,9-11 Recently, it has been shown that repressive markers, such as H3K9me3, H3K9me2 and H3K27me3, are rearranged into the nonoverlapping structural layers in SAHF. 12-14 Changes of heterochromatin organization generate a repressive chromatin environment that prevents transcription of genes that promote growth, thereby stabilize the state of senescence. 7,15 The retinoblastoma (RB) tumor suppressor is an important senesc...
32Invasiveness of cancer cells is associated with proliferation inhibition in multiple types of 33 cancers. Here, we identified the pivotal roles of Arginine methyltransferase PRMT7 in 34 promoting invasion and attenuating proliferation of breast cancer cells. PRMT7 exerted its 35 functions through binding to the scaffold protein shank2 to induce the di-methylation of shank2 36 at R240. Shank2 R240 methylation exposed ANK domain by disrupting its SPN-ANK domain 37 blockade. Moreover, shank2 R240 methylation rendered recruitment of FAK that elicited the 38 FAK auto-phosphorylation, which consequently augmented the shank2-dependent migration 39 and invasion of breast cancer cells. On the other hand, the shank2 R240 methylation impeded 40 proliferation of breast cancer cells by antagonizing the Ras-Raf binding via tethering the 41 mono-ubiquitinated H-Ras. These findings characterize the PRMT7-dependent shank2 42 methylation as a key player in mediating reciprocal switching between invasion and 43 proliferation, also point to the value of shank2 R240 methylation as a target for tumour 44 metastasis treatment strategies. Introduction 65Metastasis is the leading cause of cancer-associated death (Lambert et al., 2017). Tumour 66 cells confers a metastatic phenotype by controlling the balance between cell proliferation and 67 cell motility. It is conventionally thought that metastasis develops at least partly as a function of 68 tumour growth. Indeed, tumour size is an unfavourable prognostic marker for many kinds of 69 tumours such as squamous cell carcinoma, glioma, prostatic cancer, melanoma and breast 70 cancer, implying metastasis develops as a result of tumour cell suppresses proliferation 71 capability but increases invasion potential (Gao et al., 2005; Kemper et al., 2014; Patsos et al., 72 2010; Shiwarski et al., 2014; Whittle et al., 2015). Studies of invasive tumour cell populations 73 have shown that motile cells upregulate genes that support invasion while attenuating 74 proliferation. In glioma, EphB2 overexpression promotes migration and inhibits proliferation 75 of glioma cells by binding and activating FAK (Wang et al., 2012). In prostatic cancer, hypoxia 76 reduces SNPH expression resulting increase in ROS inhibits tumour cell proliferation, while 77 promoting increased FAK-dependent tumour cell migration and invasion (Caino et al., 2017). 78In basal cell carcinomas, p16 INK4a was up-regulated at the invasive front of the majority of basal 79 cell carcinomas with infiltrative growth patterns, followed by ceased proliferation (Svensson et 80 al., 2003). In melanoma, c-Jun was reported critical for inflammation-induced dedifferentiation 81 and played as a key driver of the transition between proliferative and invasive state (Riesenberg et al., 2015). In breast cancer, invasiveness of breast cancer cells is associated 83 with growth arrest due to p21 CIP1 upregulation (Qian et al., 2013). Similarly, snail causes the 84 loss of epithelial markers, upregulates mesenchymal markers, and impairs cell p...
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