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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