Deregulated Myc Requires MondoA/Mlx for Metabolic Reprogramming and Tumorigenesis

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2015 Feb 3

PMID 25640402

Citations 128

Authors

Patrick A Carroll

Daniel Diolaiti

Lisa McFerrin

Haiwei Gu

Danijel Djukovic

Jianhai Du

Pei Feng Cheng

Sarah Anderson

Michelle Ulrich

James B Hurley

Daniel Raftery

Donald E Ayer

Robert N Eisenman

Affiliations

Soon will be listed here.

Abstract

Deregulated Myc transcriptionally reprograms cell metabolism to promote neoplasia. Here we show that oncogenic Myc requires the Myc superfamily member MondoA, a nutrient-sensing transcription factor, for tumorigenesis. Knockdown of MondoA, or its dimerization partner Mlx, blocks Myc-induced reprogramming of multiple metabolic pathways, resulting in apoptosis. Identification and knockdown of genes coregulated by Myc and MondoA have allowed us to define metabolic functions required by deregulated Myc and demonstrate a critical role for lipid biosynthesis in survival of Myc-driven cancer. Furthermore, overexpression of a subset of Myc and MondoA coregulated genes correlates with poor outcome of patients with diverse cancers. Coregulation of cancer metabolism by Myc and MondoA provides the potential for therapeutics aimed at inhibiting MondoA and its target genes.

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References

Yuneva M, Fan T, Allen T, Higashi R, Ferraris D, Tsukamoto T . The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab. 2012; 15(2):157-70. PMC: 3282107. DOI: 10.1016/j.cmet.2011.12.015. View

Meroni G, Cairo S, Merla G, Messali S, Brent R, Ballabio A . Mlx, a new Max-like bHLHZip family member: the center stage of a novel transcription factors regulatory pathway?. Oncogene. 2000; 19(29):3266-77. DOI: 10.1038/sj.onc.1203634. View

OShea J, Ayer D . Coordination of nutrient availability and utilization by MAX- and MLX-centered transcription networks. Cold Spring Harb Perspect Med. 2013; 3(9):a014258. PMC: 3753723. DOI: 10.1101/cshperspect.a014258. View

Mendez-Lucas A, Hyrossova P, Novellasdemunt L, Vinals F, Perales J . Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) is a pro-survival, endoplasmic reticulum (ER) stress response gene involved in tumor cell adaptation to nutrient availability. J Biol Chem. 2014; 289(32):22090-102. PMC: 4139223. DOI: 10.1074/jbc.M114.566927. View

Eisen M, Spellman P, Brown P, Botstein D . Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A. 1998; 95(25):14863-8. PMC: 24541. DOI: 10.1073/pnas.95.25.14863. View

Diolaiti D, McFerrin L, Carroll P, Eisenman R . Functional interactions among members of the MAX and MLX transcriptional network during oncogenesis. Biochim Biophys Acta. 2014; 1849(5):484-500. PMC: 4241192. DOI: 10.1016/j.bbagrm.2014.05.016. View

Lin C, Loven J, Rahl P, Paranal R, Burge C, Bradner J . Transcriptional amplification in tumor cells with elevated c-Myc. Cell. 2012; 151(1):56-67. PMC: 3462372. DOI: 10.1016/j.cell.2012.08.026. View

Yuneva M, Zamboni N, Oefner P, Sachidanandam R, Lazebnik Y . Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol. 2007; 178(1):93-105. PMC: 2064426. DOI: 10.1083/jcb.200703099. View

Eberlin L, Gabay M, Fan A, Gouw A, Tibshirani R, Felsher D . Alteration of the lipid profile in lymphomas induced by MYC overexpression. Proc Natl Acad Sci U S A. 2014; 111(29):10450-5. PMC: 4115527. DOI: 10.1073/pnas.1409778111. View

10.

Conacci-Sorrell M, McFerrin L, Eisenman R . An overview of MYC and its interactome. Cold Spring Harb Perspect Med. 2014; 4(1):a014357. PMC: 3869278. DOI: 10.1101/cshperspect.a014357. View

11.

Sridharan R, Tchieu J, Mason M, Yachechko R, Kuoy E, Horvath S . Role of the murine reprogramming factors in the induction of pluripotency. Cell. 2009; 136(2):364-77. PMC: 3273494. DOI: 10.1016/j.cell.2009.01.001. View

12.

Billin A, Eilers A, Queva C, Ayer D . Mlx, a novel Max-like BHLHZip protein that interacts with the Max network of transcription factors. J Biol Chem. 1999; 274(51):36344-50. DOI: 10.1074/jbc.274.51.36344. View

13.

Oberthuer A, Berthold F, Warnat P, Hero B, Kahlert Y, Spitz R . Customized oligonucleotide microarray gene expression-based classification of neuroblastoma patients outperforms current clinical risk stratification. J Clin Oncol. 2006; 24(31):5070-8. DOI: 10.1200/JCO.2006.06.1879. View

14.

Dang C . Therapeutic targeting of Myc-reprogrammed cancer cell metabolism. Cold Spring Harb Symp Quant Biol. 2011; 76:369-74. DOI: 10.1101/sqb.2011.76.011296. View

15.

Dang C . MYC on the path to cancer. Cell. 2012; 149(1):22-35. PMC: 3345192. DOI: 10.1016/j.cell.2012.03.003. View

16.

Peterson C, Stoltzman C, Sighinolfi M, Han K, Ayer D . Glucose controls nuclear accumulation, promoter binding, and transcriptional activity of the MondoA-Mlx heterodimer. Mol Cell Biol. 2010; 30(12):2887-95. PMC: 2876681. DOI: 10.1128/MCB.01613-09. View

17.

Evan G, Wyllie A, GILBERT C, Littlewood T, Land H, Brooks M . Induction of apoptosis in fibroblasts by c-myc protein. Cell. 1992; 69(1):119-28. DOI: 10.1016/0092-8674(92)90123-t. View

18.

Wise D, DeBerardinis R, Mancuso A, Sayed N, Zhang X, Pfeiffer H . Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci U S A. 2008; 105(48):18782-7. PMC: 2596212. DOI: 10.1073/pnas.0810199105. View

19.

Duran R, Oppliger W, Robitaille A, Heiserich L, Skendaj R, Gottlieb E . Glutaminolysis activates Rag-mTORC1 signaling. Mol Cell. 2012; 47(3):349-58. DOI: 10.1016/j.molcel.2012.05.043. View

20.

Morrish F, Noonan J, Perez-Olsen C, Gafken P, Fitzgibbon M, Kelleher J . Myc-dependent mitochondrial generation of acetyl-CoA contributes to fatty acid biosynthesis and histone acetylation during cell cycle entry. J Biol Chem. 2010; 285(47):36267-74. PMC: 2978554. DOI: 10.1074/jbc.M110.141606. View