NCYM promotes calpain-mediated Myc-nick production in human MYCN-amplified neuroblastoma cells

Watanabe, Shôji; Suenaga, Yusuke; Kaneko, Yoshiki; Islam, S.M. Rafiqul; Alagu, Jennifer; Yokoi, Sana; Nio, Masaki; Nakagawara, Akira

doi:10.1016/j.bbrc.2015.04.050

Cited by 22 publications

(22 citation statements)

References 27 publications

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“…We had previously shown that several distinct tumor types express high levels of MYC-nick (15,16). Moreover, a recent study reported that MYC-nick expression is associated with survival of neuroblastoma cells (55).…”

Section: Discussionmentioning

confidence: 99%

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

Anderson

Poudel

Roh-Johnson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussionmentioning

confidence: 99%

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

Anderson

Poudel

Roh-Johnson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, a post-transcriptional mRNA stabilization mechanism has been found for p53 expression due to double-stranding p53 mRNA with the Wrap53 gene mRNA [ 8 ], which might be relevant in many cancers. High expression of the MYCN cis-antisense gene NCYM is associated with poor prognosis in neuroblastoma via promotion of production of anti-apoptotic protein Myc-nick [ 18 ]. Sharing a bidirectional promoter leads to coordination of gene expression levels for BAL/BBAP SAGP, providing optimal interaction of their protein products in chemoresistant, diffuse, large-cell lymphomas [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Sense-antisense gene-pairs in breast cancer and associated pathological pathways

et al. 2015

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More than 30% of human protein-coding genes form hereditary complex genome architectures composed of sense-antisense (SA) gene pairs (SAGPs) transcribing their RNAs from both strands of a given locus. Such architectures represent important novel components of genome complexity contributing to gene expression deregulation in cancer cells. Therefore, the architectures might be involved in cancer pathways and, in turn, be used for novel drug targets discovery. However, the global roles of SAGPs in cancer pathways has not been studied. Here we investigated SAGPs associated with breast cancer (BC)-related pathways using systems biology, prognostic survival and experimental methods. Gene expression analysis identified 73 BC-relevant SAGPs that are highly correlated in BC. Survival modelling and metadata analysis of the 1161 BC patients allowed us to develop a novel patient prognostic grouping method selecting the 12 survival-significant SAGPs. The qRT-PCR-validated 12-SAGP prognostic signature reproducibly stratified BC patients into low- and high-risk prognostic subgroups. The 1381 SAGP-defined differentially expressed genes common across three studied cohorts were identified. The functional enrichment analysis of these genes revealed the GABPA gene network, including BC-relevant SAGPs, specific gene sets involved in cell cycle, spliceosomal and proteasomal pathways. The co-regulatory function of GABPA in BC cells was supported using siRNA knockdown studies. Thus, we demonstrated SAGPs as the synergistically functional genome architectures interconnected with cancer-related pathways and associated with BC patient clinical outcomes. Taken together, SAGPs represent an important component of genome complexity which can be used to identify novel aspects of coordinated pathological gene networks in cancers.

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“…(32) Therefore, overexpression of reprogramming factors may contribute to chemoresistance in MYCN-non amplified SH-IN cells, possibly by induction of these stem-cell related genes. (29)(30)(31)(32)35,36) Our present findings indicate that partially reprogrammed NB cells could be a valuable in vitro model for understanding how NB cells maintain plasticity and aggressiveness.…”

Section: Discussionmentioning

confidence: 60%

“…Previous reports suggest that the expression level of MYCN is not associated with poor prognosis in MYCN non‐amplified NBs, while the level of NCYM is associated with poor prognosis . Therefore, overexpression of reprogramming factors may contribute to chemoresistance in MYCN ‐non amplified SH‐IN cells, possibly by induction of these stem‐cell related genes …”

Section: Discussionmentioning

confidence: 97%

Sendai virus‐mediated expression of reprogramming factors promotes plasticity of human neuroblastoma cells

et al. 2015

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Neuroblastoma (NB) is the most common extracranial solid tumor that originates from multipotent neural crest cells. NB cell populations that express embryonic stem cell-associated genes have been identified and shown to retain a multipotent phenotype. However, whether somatic reprogramming of NB cells can produce similar stem-cell like populations is unknown. Here, we sought to reprogram NB cell lines using an integration-free Sendai virus vector system. Of four NB cell lines examined, only SH-IN cells formed induced pluripotent stem cell-like colonies (SH-IN 4F colonies) at approximately 6 weeks following transduction. These SH-IN 4F colonies were alkaline phosphatase-positive. Array comparative genomic hybridization analysis indicated identical genomic aberrations in the SH-IN 4F cells as in the parental cells. SH-IN 4F cells had the ability to differentiate into the three embryonic germ layers in vitro, but rather formed NBs in vivo. Furthermore, SH-IN 4F cells exhibited resistance to cisplatin treatment and differentiated into endothelial-like cells expressing CD31 in the presence of vascular endothelial growth factor. These results suggest that SH-IN 4F cells are partially reprogrammed NB cells, and could be a suitable model for investigating the plasticity of aggressive tumors.

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NCYM promotes calpain-mediated Myc-nick production in human MYCN-amplified neuroblastoma cells

Cited by 22 publications

References 27 publications

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

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

Sense-antisense gene-pairs in breast cancer and associated pathological pathways

Sendai virus‐mediated expression of reprogramming factors promotes plasticity of human neuroblastoma cells

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