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The metabolic state of a cell is influenced by cell-extrinsic factors, including nutrient availability and growth factor signaling. Here, we present extracellular matrix (ECM) remodeling as another fundamental node of cell-extrinsic metabolic regulation. Unbiased analysis of glycolytic drivers identified the hyaluronan-mediated motility receptor as being among the most highly correlated with glycolysis in cancer. Confirming a mechanistic link between the ECM component hyaluronan and metabolism, treatment of cells and xenografts with hyaluronidase triggers a robust increase in glycolysis. This is largely achieved through rapid receptor tyrosine kinase-mediated induction of the mRNA decay factor ZFP36, which targets TXNIP transcripts for degradation. Because TXNIP promotes internalization of the glucose transporter GLUT1, its acute decline enriches GLUT1 at the plasma membrane. Functionally, induction of glycolysis by hyaluronidase is required for concomitant acceleration of cell migration. This interconnection between ECM remodeling and metabolism is exhibited in dynamic tissue states, including tumorigenesis and embryogenesis.

Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN.

UnlabelledDeregulated glucose metabolism fulfills the energetic and biosynthetic requirements for tumor growth driven by oncogenes. Because inhibition of oncogenic BRAF causes profound reductions in glucose uptake and a strong clinical benefit in BRAF-mutant melanoma, we examined the role of energy metabolism in responses to BRAF inhibition. We observed pronounced and consistent decreases in glycolytic activity in BRAF-mutant melanoma cells. Moreover, we identified a network of BRAF-regulated transcription factors that control glycolysis in melanoma cells. Remarkably, this network of transcription factors, including hypoxia-inducible factor-1α, MYC, and MONDOA (MLXIP), drives glycolysis downstream of BRAF(V600), is critical for responses to BRAF inhibition, and is modulated by BRAF inhibition in clinical melanoma specimens. Furthermore, we show that concurrent inhibition of BRAF and glycolysis induces cell death in BRAF inhibitor (BRAFi)-resistant melanoma cells. Thus, we provide a proof-of-principle for treatment of melanoma with combinations of BRAFis and glycolysis inhibitors.SignificanceBRAF is suppress glycolysis and provide strong clinical benefi t in BRAF V600 melanoma. We show that BRAF inhibition suppresses glycolysis via a network of transcription factors that are critical for complete BRAFi responses. Furthermore, we provide evidence for the clinical potential of therapies that combine BRAFis with glycolysis inhibitors.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2007.07.034 Byline: Christopher L. Pickett, Kevin T. Breen, Donald E. Ayer Keywords: Myc; Mondo; Semaphorin; Plexin; Wnt; [beta]-catenin; Cell migration; ECM Abstract: Myc and Mondo proteins are key regulators of cell growth, proliferation, and energy metabolism, yet often overlooked is their vital role in cell migration. Complex networks of protein-protein and protein-DNA interactions control the transcriptional activity of Myc and MondoA confounding their functional analysis in higher eukaryotes. Here we report the identification of the transcriptional activation arm of a simplified Myc-like network in Caenorhabditis elegans. This network comprises an Mlx ortholog, named MXL-2 for Max-like 2, and a protein that has sequence features of both Myc and Mondo proteins, named MML-1 for Myc and Mondo-like 1. MML-1/MXL-2 complexes have a primary function in regulating migration of the ray 1 precursor cells in the male tail. MML-1/MXL-2 complexes control expression of ECM components in the non-migratory epidermis, which we propose contributes to the substratum required for migration of the neighboring ray 1 precursor cells. Furthermore, we show that pro-migratory Wnt/[beta]-catenin and semaphorin signaling pathways interact genetically with MML-1/MXL-2 to determine ray 1 position. This first functional analysis of the Myc superfamily in C. elegans suggests that MondoA and Myc may have more predominant roles in cell migration than previously appreciated, and their cooperation with other pro-migratory pathways provides a more integrated view of their role in cell migration. Author Affiliation: Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, Room 4365, Salt Lake City, UT 84112-5550, USA Article History: Received 25 April 2007; Revised 6 July 2007; Accepted 14 July 2007

Nuclear magnetic resonance structure of the Mad-Sin3 complex resulting from PAH2 domain of the mammalian corepressor Sin3A and the transrepression domain SID of human Mad1 exhibits an unusual left-handed four helix for the former and an amphipathic alpha helix for the the latter.

SMRT, Sin3, and N-CoR establish protein-to-protein link between deacetylases and DNA-bound repressors hence, the term corepressors. These corepressors interact with each other and influence nuclear receptor to remodel chromatin structure without altering the regulatory complex through the help of hormone dependent adaptor HDAC. Transcriptional repression is achieved through regulation of chromatin structure resulting in an opposed cellular differentiation.

Histone deacetylation plays a direct role in mSin3A-mediated transcriptional repression as demonstrated by the use of specific histone deacetylase inhibitor trapoxin in transfected cells. An increase in the transcriptional activity of an mSin3A-silenced reporter gene upon treatment in vivo with trapoxin implies that full transcriptional repressionby mSin3A requires histone deacetylation.

A study of the factors that facilitate Mad-Max transcriptional inhibition reveals that the repression occurs through the anchoring of mSin3 to DNA as corepressors and indicates the preservation of the transcriptional repression from yeast to mammals. Two mammalian cDNAs that code for Mad-binding proteins exhibit sequence homology with Sin3 and possess four conserved paired amphipathic helix domains. The Mad-Max E box-binding site is identified by ternary complexes formed by Mad-Max and mSin3. Interactions with mSin3 proteins are abolished and Mad transcriptional repression is inhibited by point mutations in the amphipathic alpha-helical region.

The Mad protein has been identified as a new member of the basic-helix-loop-helix-Zip protein family. The procedure for identification consisted of screening the lambdagt11 expression library with radiolabeled Max protein. A sequence-specific DNA-binding complex, Mad-Max, was observed for the human Mad protein. The Mad-Max heterodimeric complex may be involved in transcriptional repression.

Oncogenic Ras upregulates aerobic glycolysis to meet the bioenergetic and biosynthetic demands of rapidly growing cells. In contrast, Thioredoxin interacting protein (TXNIP) is a potent inhibitor of glucose uptake and is frequently downregulated in human cancers. Our lab previously discovered that Ras activation suppresses TXNIP transcription and translation. In this report, we developed a system to study how Ras affects TXNIP translation in the absence of transcriptional affects. We show that whereas Ras drives a global increase in protein translation, it suppresses TXNIP protein synthesis by reducing the rate at which ribosomes transit the coding region of TXNIP mRNA. To investigate the underlying mechanism(s), we randomized or optimized the codons in the TXNIP message without altering the TXNIP primary amino acid sequence. Translation from these mRNA variants is still repressed by Ras, intimating that mRNA secondary structure, miRNAs, RNA binding proteins, or codon usage do not contribute to the blockade of TXNIP synthesis. Rather, we show that the N-terminus of the growing TXNIP polypeptide is the target for Ras-dependent translational repression. Our work demonstrates how Ras suppresses TXNIP translation elongation in the face of a global upregulation of protein synthesis and provides new insight into Ras-dependent metabolic reprogramming. [ABSTRACT FROM AUTHOR]