MYC-nick promotes cell migration by inducing fascin expression and Cdc42 activation

Abstract

MYC-nick is a cytoplasmic, transcriptionally inactive member of the MYC oncoprotein family, generated by a proteolytic cleavage of full-length MYC. MYC-nick promotes migration and survival of cells in response to chemotherapeutic agents or withdrawal of glucose. Here we report that MYC-nick is abundant in colonic and intestinal tumors derived from mouse models with mutations in the Wnt, TGF-β, and PI3K pathways. Moreover, MYC-nick is elevated in colon cancer cells deleted for FBWX7, which encodes the major E3 ligase of full-length MYC frequently mutated in colorectal cancers. MYC-nick promotes the migration of colon cancer cells assayed in 3D cultures or grown as xenografts in a zebrafish metastasis model. MYC-nick accelerates migration by activating the Rho GTPase Cdc42 and inducing fascin expression. MYC-nick, fascin, and Cdc42 are frequently up-regulated in cells present at the invasive front of human colorectal tumors, suggesting a coordinated role for these proteins in tumor migration. (9). As one of the major determinants of MYC's transcriptional function, MBII recruits coactivator complexes including histone acetyltransferases (HATs), such as GCN5 (10) and Tip60 (11). MYC is a very short-lived protein, and multiple E3 ligases have been implicated in regulating MYC protein turnover through the ubiquitin-proteasome system (12). Importantly, MYC levels have been demonstrated to be elevated in cancer cells because of prolonged protein halflife (13,14).MYC is also targeted by calpain proteases in the cytoplasm (15-17). Calpain-mediated scission of MYC degrades its C terminus, which inactivates MYC's transcriptional functions. Furthermore, the cleavage generates MYC-nick, a truncated product that retains MBI-MBIII (16). Although MYC-nick is expressed in most cultured cells and in mouse tissues, its levels are increased in cells cultured under conditions leading to stress, such as high cell density, nutrient deprivation, and hypoxia (15,16,18). Recently, we found that the conversion of MYC into MYC-nick occurs in the cytoplasm of colon cancer cells, where it promotes cell survival and motility (15). Here we demonstrate that MYC-nick promotes cell migration and invasion by inducing fascin expression and activating the Rho GTPase Cdc42 in distinct models of colon cancer. Results MYC-Nick Is Expressed in Intestinal and Colon Lesions in MouseCancer Models Driven by Mutations in Apc, Tgfbr2, and Kras. We had previously shown that MYC-nick is expressed in cancer cell lines and cancers arising from different primary tissues (15). To extend those studies, we examined the expression of MYC variants in mouse colon cancers derived from distinct models of intestinal cancer. Most colorectal carcinomas carry mutations that affect Wnt, TGF-β, and PI3K signaling pathways (19,20). We compared the expression of MYC in tumors arising from models containing (i) a truncation in one of the alleles of Apc (Apc 1638/+ ; labeled ATT); (ii) Pten and Tgfbr2 deletions combined (PPVcTT); (iii) Apc truncation in combination with Tgfbr2 dele...

CXCL12 and MYC control energy metabolism to support adaptive responses after kidney injury

“…MYC belongs to a family of transcription factors that regulates the expression of a large number of target genes, controlling almost every aspect of cell proliferation, differentiation, and metabolism. MYC promotes cell migration and invasion, for example by activating Rho GTPases 39 , but can also display anti-migratory effects through repression of CCL5/RANTES 40 . Since MYC enhances the promoter activity of CXCR4 41 , we examined whether Cxcr4b can act down-stream of myca in the zebrafish pronephros repair model.…”

A function of fascin1 in the colony formation of mouse embryonic stem cells

“…11 In addition, MYC-nick regulates cancer cell migration by enhancing the expression of fascin1 and subsequently promoting the stabilization of actin filaments. 39 Here, we found that LIF and CHIR99021 significantly enhanced fascin1 expression in mESC.…”

Overexpression of PRDM5 promotes acute myeloid leukemia cell proliferation and migration by activating the JNK pathway

“…Interestingly, we observed that although c‐Myc expression was downregulated in OE cells, the JNK inhibitor increased the expression of c‐Myc. c‐Myc has been shown to be a protooncogene that modulates numerous cancer cell behaviors, including proliferation, differentiation, migration, and genomic instability . Recently, Ma et al demonstrated that c‐Myc also suppressed cell migration in Drosophila and human lung adenocarcinoma cell lines in a JNK‐dependent manner .…”

“…c-Myc has been shown to be a protooncogene that modulates numerous cancer cell behaviors, including proliferation, differentiation, migration, and genomic instability. [33][34][35] Recently, Ma et al demonstrated that c-Myc also suppressed cell migration in Drosophila and human lung adenocarcinoma cell lines in a JNK-dependent manner. 36 Consistent with the results of that research, our results indicated that suppressed JNK activity was positively correlated with c-Myc expression.…”