MYC Phosphorylation at Novel Regulatory Regions Suppresses Transforming Activity

Abstract

Despite its central role in human cancer, MYC deregulation is insufficient by itself to transform cells. Because inherent mechanisms of neoplastic control prevent precancerous lesions from becoming fully malignant, identifying transforming alleles of MYC that bypass such controls may provide fundamental insights into tumorigenesis. To date, the only activated allele of MYC known is T58A, the study of which led to identification of the tumor suppressor FBXW7 and its regulator USP28 as a novel therapeutic target. In this study, we screened a panel of MYC phosphorylation mutants for their ability to promote anchorage-independent colony growth of human MCF10A mammary epithelial cells, identifying S71A/S81A and T343A/S344A/S347A/S348A as more potent oncogenic mutants compared with wild-type (WT) MYC. The increased cell-transforming activity of these mutants was confirmed in SH-EP neuroblastoma cells and in three-dimensional MCF10A acini. Mechanistic investigations initiated by a genome-wide mRNA expression analysis of MCF10A acini identified 158 genes regulated by the mutant MYC alleles, compared with only 112 genes regulated by both WT and mutant alleles. Transcriptional gain-of-function was a common feature of the mutant alleles, with many additional genes uniquely dysregulated by individual mutant. Our work identifies novel sites of negative regulation in MYC and thus new sites for its therapeutic attack. Cancer Res; 73(21); 6504-15. Ó2013 AACR.

Clinical and Biologic Significance of MYC Genetic Mutations in De Novo Diffuse Large B-cell Lymphoma

“…Individual analysis of particular mutation types showed differential expressed genes involved in proliferation, metabolism and apoptosis (Supplementary Figure S2D–G, Supplementary Table S7), but the significance of these analyses was hindered by small numbers and the heterogeneity of the MUT-Myc cases likely because some patients carried multiple mutations. Notably these signatures included genes involved in Ras/Rho GTPase signaling which interacts with the Myc T58 residue (10,13) and can cooperate with Myc during tumorigenesis (32). …”

“…Functional studies indicated that Myc T58 mutants had increased transforming ability, increased Myc stability, and decreased proapoptotic ability, owing to alterations in posttranslational modifications of Myc. In contrast, S62 mutations, which are also frequent in the MBI motif and are associated with increased Myc expression, lead to decreased transforming ability without affecting apoptosis (10,13–17); the F138C mutation in the Myc box II (MBII) motif (128–143aa) decreases both transformation and apoptosis (18); and deletion of residues 188–199 in the Myc box III (MBIII) motif correlates with increased response to apoptosis and decreased tumorigenic ability in vivo (19). Moreover, somatic mutations exist in noncoding MYC exon I (5´ untranslated region [UTR]) (20,21) and within intron 1 near the exon 1 boundary (22), which may represent another pathogenic mechanism by deregulating MYC expression (20).…”

Polyamine Antagonist Therapies Inhibit Neuroblastoma Initiation and Progression

“…This evolutionarily conserved role in protein synthesis is critical to Myc oncogenesis and its inhibition has synthetic-lethal consequences (44). Among the genes highly regulated by MYC are polyamine homeostatic enzymes, constituting a core expression program downstream of MYC in transformation (45).…”

Genome-Wide Transcriptome Analysis of Estrogen Receptor-Positive and Human Epithelial Growth Factor Receptor 2-Positive Breast Cancers by Ribonucleic Acid Sequencing

“…GO and KEGG enrichment analysis of DEGs revealed the upregulation of transcription and immune systems, as well as downregulation in the nitrogen compound metabolic process, the programmed cell death, the cellular biosynthetic process, and MAPK signaling pathway in both subtypes of breast cancers. In these dysregulated biological processes, we found certain genes have been shown to associate with breast cancers, such as the upregulation in the expression of immune-related gene VAV1 indicated an increasing immune response to cancer formation in breast cancers [25], and the downregulation of MYC expression in the process of programmed cell death might lead to loss of negative regulation of cancer progression in breast cancers [26, 27]. Towards the differences between the 2 subtypes, HER2+ breast cancer was shown to have higher cell proliferation ability and higher metastatic ability, clearly supported by higher activities of genes (e.g., KIF23 , CLSPN , NEK2 , TMX1, and HMGB1 ) of cell cycle, nuclear division, DNA replication, and the lower activity of certain genes (e.g., AEBP1 , BCAR1, and PCDHGA9 ) of cell adhesion in HER2+ breast cancers compared to the ER+ subtype.…”