The MYC Oncogene Cooperates with Sterol-Regulated Element-Binding Protein to Regulate Lipogenesis Essential for Neoplastic Growth

Arvin M. Gouw; Katherine Margulis; Natalie S. Liu; Sudha J. Raman; Anthony Mancuso; Georgia G. Toal; Ling Tong; Adriane Mosley; Annie L. Hsieh; Delaney K. Sullivan; Zachary E. Stine; Brian J. Altman; Almut Schulze; Chi V. Dang; Richard N. Zare; Dean W. Felsher

doi:10.1016/j.cmet.2019.07.012

The MYC Oncogene Cooperates with Sterol-Regulated Element-Binding Protein to Regulate Lipogenesis Essential for Neoplastic Growth

Arvin M. Gouw, Katherine Margulis, Natalie S. Liu, Sudha J. Raman, Anthony Mancuso, Georgia G. Toal, Ling Tong, Adriane Mosley, Annie L. Hsieh, Delaney K. Sullivan, Zachary E. Stine, Brian J. Altman, Almut Schulze, Chi V. Dang^*, Richard N. Zare, Dean W. Felsher

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

98 Scopus citations

Abstract

Lipid metabolism is frequently perturbed in cancers, but the underlying mechanism is unclear. We present comprehensive evidence that oncogene MYC, in collaboration with transcription factor sterol-regulated element-binding protein (SREBP1), regulates lipogenesis to promote tumorigenesis. We used human and mouse tumor-derived cell lines, tumor xenografts, and four conditional transgenic mouse models of MYC-induced tumors to show that MYC regulates lipogenesis genes, enzymes, and metabolites. We found that MYC induces SREBP1, and they collaborate to activate fatty acid (FA) synthesis and drive FA chain elongation from glucose and glutamine. Further, by employing desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we observed in vivo lipidomic changes upon MYC induction across different cancers, for example, a global increase in glycerophosphoglycerols. After inhibition of FA synthesis, tumorigenesis was blocked, and tumors regressed in both xenograft and primary transgenic mouse models, revealing the vulnerability of MYC-induced tumors to the inhibition of lipogenesis. Gouw and Margulis et al. present comprehensive evidence that the oncogene MYC collaborates with the transcription factor SREBP1 in controlling lipogenesis to promote tumorigenesis. Utilizing multiple MYC-induced tumor models, they both identify key lipogenesis genes, enzymes, and metabolites affected by MYC and expose the vulnerability of MYC cancers to lipogenesis inhibition.

Original language	American English
Pages (from-to)	556-572.e5
Journal	Cell Metabolism
Volume	30
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2019.07.012
State	Published - 3 Sep 2019
Externally published	Yes

Bibliographical note

Funding Information:
We thank current and former members of the Dang, Felsher, Schulze, and Zare laboratories for their helpful suggestions during this project. We thank Livia Eberlin, Emelyn Shroff, Michael Wolfgang, Yunqi Lu, and Anne Le for their help. A.M.G. and K.M. are grateful to the Stanford Cancer Translational Nanotechnology Training (TNT) T32 training grant funded by the National Cancer Institute ( T32 CA196585 ) and the Stanford Center of Molecular Analysis and Design , respectively. This work is supported by the National Institutes of Health under R01 CA184384 (D.W.F. and R.N.Z.), U01 CA188383 (D.W.F.), R01 CA208735 PQ7 (D.W.F.), R01 CA051497 (C.V.D.), R01 CA057341 (C.V.D.), and the German Research Foundation ( SCHU2670 ).

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

ChIP
MYC
MYC conditional transgenic mouse models
RNA-seq
SREBP1
acetyl-CoA carboxylase A inhibition
carbon tracing
fatty acid synthesis
glycerophosphoglycerols
mass spectrometry imaging
nuclear run-on

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2019.07.012

Cite this

Gouw, A. M., Margulis, K., Liu, N. S., Raman, S. J., Mancuso, A., Toal, G. G., Tong, L., Mosley, A., Hsieh, A. L., Sullivan, D. K., Stine, Z. E., Altman, B. J., Schulze, A., Dang, C. V., Zare, R. N., & Felsher, D. W. (2019). The MYC Oncogene Cooperates with Sterol-Regulated Element-Binding Protein to Regulate Lipogenesis Essential for Neoplastic Growth. Cell Metabolism, 30(3), 556-572.e5. https://doi.org/10.1016/j.cmet.2019.07.012

@article{745b578a710b4530bc56a1ea7fac07ed,

title = "The MYC Oncogene Cooperates with Sterol-Regulated Element-Binding Protein to Regulate Lipogenesis Essential for Neoplastic Growth",

abstract = "Lipid metabolism is frequently perturbed in cancers, but the underlying mechanism is unclear. We present comprehensive evidence that oncogene MYC, in collaboration with transcription factor sterol-regulated element-binding protein (SREBP1), regulates lipogenesis to promote tumorigenesis. We used human and mouse tumor-derived cell lines, tumor xenografts, and four conditional transgenic mouse models of MYC-induced tumors to show that MYC regulates lipogenesis genes, enzymes, and metabolites. We found that MYC induces SREBP1, and they collaborate to activate fatty acid (FA) synthesis and drive FA chain elongation from glucose and glutamine. Further, by employing desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we observed in vivo lipidomic changes upon MYC induction across different cancers, for example, a global increase in glycerophosphoglycerols. After inhibition of FA synthesis, tumorigenesis was blocked, and tumors regressed in both xenograft and primary transgenic mouse models, revealing the vulnerability of MYC-induced tumors to the inhibition of lipogenesis. Gouw and Margulis et al. present comprehensive evidence that the oncogene MYC collaborates with the transcription factor SREBP1 in controlling lipogenesis to promote tumorigenesis. Utilizing multiple MYC-induced tumor models, they both identify key lipogenesis genes, enzymes, and metabolites affected by MYC and expose the vulnerability of MYC cancers to lipogenesis inhibition.",

keywords = "ChIP, MYC, MYC conditional transgenic mouse models, RNA-seq, SREBP1, acetyl-CoA carboxylase A inhibition, carbon tracing, fatty acid synthesis, glycerophosphoglycerols, mass spectrometry imaging, nuclear run-on",

author = "Gouw, {Arvin M.} and Katherine Margulis and Liu, {Natalie S.} and Raman, {Sudha J.} and Anthony Mancuso and Toal, {Georgia G.} and Ling Tong and Adriane Mosley and Hsieh, {Annie L.} and Sullivan, {Delaney K.} and Stine, {Zachary E.} and Altman, {Brian J.} and Almut Schulze and Dang, {Chi V.} and Zare, {Richard N.} and Felsher, {Dean W.}",

note = "Funding Information: We thank current and former members of the Dang, Felsher, Schulze, and Zare laboratories for their helpful suggestions during this project. We thank Livia Eberlin, Emelyn Shroff, Michael Wolfgang, Yunqi Lu, and Anne Le for their help. A.M.G. and K.M. are grateful to the Stanford Cancer Translational Nanotechnology Training (TNT) T32 training grant funded by the National Cancer Institute ( T32 CA196585 ) and the Stanford Center of Molecular Analysis and Design , respectively. This work is supported by the National Institutes of Health under R01 CA184384 (D.W.F. and R.N.Z.), U01 CA188383 (D.W.F.), R01 CA208735 PQ7 (D.W.F.), R01 CA051497 (C.V.D.), R01 CA057341 (C.V.D.), and the German Research Foundation ( SCHU2670 ). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = sep,

day = "3",

doi = "10.1016/j.cmet.2019.07.012",

language = "American English",

volume = "30",

pages = "556--572.e5",

journal = "Cell Metabolism",

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Gouw, AM, Margulis, K, Liu, NS, Raman, SJ, Mancuso, A, Toal, GG, Tong, L, Mosley, A, Hsieh, AL, Sullivan, DK, Stine, ZE, Altman, BJ, Schulze, A, Dang, CV, Zare, RN & Felsher, DW 2019, 'The MYC Oncogene Cooperates with Sterol-Regulated Element-Binding Protein to Regulate Lipogenesis Essential for Neoplastic Growth', Cell Metabolism, vol. 30, no. 3, pp. 556-572.e5. https://doi.org/10.1016/j.cmet.2019.07.012

TY - JOUR

T1 - The MYC Oncogene Cooperates with Sterol-Regulated Element-Binding Protein to Regulate Lipogenesis Essential for Neoplastic Growth

AU - Gouw, Arvin M.

AU - Margulis, Katherine

AU - Liu, Natalie S.

AU - Raman, Sudha J.

AU - Mancuso, Anthony

AU - Toal, Georgia G.

AU - Tong, Ling

AU - Mosley, Adriane

AU - Hsieh, Annie L.

AU - Sullivan, Delaney K.

AU - Stine, Zachary E.

AU - Altman, Brian J.

AU - Schulze, Almut

AU - Dang, Chi V.

AU - Zare, Richard N.

AU - Felsher, Dean W.

N1 - Funding Information: We thank current and former members of the Dang, Felsher, Schulze, and Zare laboratories for their helpful suggestions during this project. We thank Livia Eberlin, Emelyn Shroff, Michael Wolfgang, Yunqi Lu, and Anne Le for their help. A.M.G. and K.M. are grateful to the Stanford Cancer Translational Nanotechnology Training (TNT) T32 training grant funded by the National Cancer Institute ( T32 CA196585 ) and the Stanford Center of Molecular Analysis and Design , respectively. This work is supported by the National Institutes of Health under R01 CA184384 (D.W.F. and R.N.Z.), U01 CA188383 (D.W.F.), R01 CA208735 PQ7 (D.W.F.), R01 CA051497 (C.V.D.), R01 CA057341 (C.V.D.), and the German Research Foundation ( SCHU2670 ). Publisher Copyright: © 2019 Elsevier Inc.

PY - 2019/9/3

Y1 - 2019/9/3

N2 - Lipid metabolism is frequently perturbed in cancers, but the underlying mechanism is unclear. We present comprehensive evidence that oncogene MYC, in collaboration with transcription factor sterol-regulated element-binding protein (SREBP1), regulates lipogenesis to promote tumorigenesis. We used human and mouse tumor-derived cell lines, tumor xenografts, and four conditional transgenic mouse models of MYC-induced tumors to show that MYC regulates lipogenesis genes, enzymes, and metabolites. We found that MYC induces SREBP1, and they collaborate to activate fatty acid (FA) synthesis and drive FA chain elongation from glucose and glutamine. Further, by employing desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we observed in vivo lipidomic changes upon MYC induction across different cancers, for example, a global increase in glycerophosphoglycerols. After inhibition of FA synthesis, tumorigenesis was blocked, and tumors regressed in both xenograft and primary transgenic mouse models, revealing the vulnerability of MYC-induced tumors to the inhibition of lipogenesis. Gouw and Margulis et al. present comprehensive evidence that the oncogene MYC collaborates with the transcription factor SREBP1 in controlling lipogenesis to promote tumorigenesis. Utilizing multiple MYC-induced tumor models, they both identify key lipogenesis genes, enzymes, and metabolites affected by MYC and expose the vulnerability of MYC cancers to lipogenesis inhibition.

AB - Lipid metabolism is frequently perturbed in cancers, but the underlying mechanism is unclear. We present comprehensive evidence that oncogene MYC, in collaboration with transcription factor sterol-regulated element-binding protein (SREBP1), regulates lipogenesis to promote tumorigenesis. We used human and mouse tumor-derived cell lines, tumor xenografts, and four conditional transgenic mouse models of MYC-induced tumors to show that MYC regulates lipogenesis genes, enzymes, and metabolites. We found that MYC induces SREBP1, and they collaborate to activate fatty acid (FA) synthesis and drive FA chain elongation from glucose and glutamine. Further, by employing desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we observed in vivo lipidomic changes upon MYC induction across different cancers, for example, a global increase in glycerophosphoglycerols. After inhibition of FA synthesis, tumorigenesis was blocked, and tumors regressed in both xenograft and primary transgenic mouse models, revealing the vulnerability of MYC-induced tumors to the inhibition of lipogenesis. Gouw and Margulis et al. present comprehensive evidence that the oncogene MYC collaborates with the transcription factor SREBP1 in controlling lipogenesis to promote tumorigenesis. Utilizing multiple MYC-induced tumor models, they both identify key lipogenesis genes, enzymes, and metabolites affected by MYC and expose the vulnerability of MYC cancers to lipogenesis inhibition.

KW - ChIP

KW - MYC

KW - MYC conditional transgenic mouse models

KW - RNA-seq

KW - SREBP1

KW - acetyl-CoA carboxylase A inhibition

KW - carbon tracing

KW - fatty acid synthesis

KW - glycerophosphoglycerols

KW - mass spectrometry imaging

KW - nuclear run-on

UR - http://www.scopus.com/inward/record.url?scp=85071370155&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2019.07.012

DO - 10.1016/j.cmet.2019.07.012

M3 - Article

C2 - 31447321

AN - SCOPUS:85071370155

SN - 1550-4131

VL - 30

SP - 556-572.e5

JO - Cell Metabolism

JF - Cell Metabolism

IS - 3

ER -

The MYC Oncogene Cooperates with Sterol-Regulated Element-Binding Protein to Regulate Lipogenesis Essential for Neoplastic Growth

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

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