EGFR Mutation-Induced Alternative Splicing of Max Contributes to Growth of Glycolytic Tumors in Brain Cancer

被引：153

作者：

Babic, Ivan ^{[1
]}

Anderson, Erik S. ^{[7
,8
,9
]}

Tanaka, Kazuhiro ^{[2
]}

Guo, Deliang ^{[3
]}

Masui, Kenta ^{[1
]}

Li, Bing ^{[10
]}

Zhu, Shaojun ^{[6
]}

Gu, Yuchao ^{[1
,6
]}

Villa, Genaro R. ^{[1
,6
,9
]}

Akhavan, David ^{[6
,9
]}

Nathanson, David ^{[6
]}

Gini, Beatrice ^{[1
]}

Mareninov, Sergey ^{[5
]}

Li, Rui ^{[6
]}

Camacho, Carolina Espindola ^{[6
]}

Kurdistani, Siavash K. ^{[10
]}

Eskin, Ascia ^{[11
]}

Nelson, Stanley F. ^{[11
]}

Yong, William H. ^{[5
]}

Cavenee, Webster K. ^{[1
,13
]}

Cloughesy, Timothy F. ^{[12
]}

Christofk, Heather R. ^{[6
]}

Black, Douglas L. ^{[4
,7
]}

Mische, Paul S. ^{[1
,13
,14
]}

机构：

[1] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA

[2] Kobe Univ, Dept Neurosurg, Kobe, Hyogo 6500017, Japan

[3] Ohio State Univ, Med Ctr, James Comprehens Canc Ctr, Dept Radiat Oncol, Columbus, OH 43210 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Howard Hughes Med Inst, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

[6] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[7] Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Mol Genet & Immunol, Los Angeles, CA 90095 USA

[8] Univ Calif Los Angeles, David Geffen Sch Med, UCLA Mol Biol Interdept Grad Program, Los Angeles, CA 90095 USA

[9] Univ Calif Los Angeles, David Geffen Sch Med, UCLA Med Scientist Training Program, Los Angeles, CA 90095 USA

[10] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA

[11] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[12] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA

[13] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA

[14] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA

来源：

CELL METABOLISM | 2013年 / 17卷 / 06期

基金：

美国国家卫生研究院;

关键词：

INTEGRATED GENOMIC ANALYSIS; PYRUVATE-KINASE; CELL; MYC; EXPRESSION; GLIOMA; FORMS; M2; GLIOBLASTOMAS; METABOLISM;

D O I：

10.1016/j.cmet.2013.04.013

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Alternative splicing contributes to diverse aspects of cancer pathogenesis including altered cellular metabolism, but the specificity of the process or its consequences are not well understood. We characterized genome-wide alternative splicing induced by the activating EGFRvIII mutation in glioblastoma (GBM). EGFRvIII upregulates the heterogeneous nuclear ribonucleoprotein (hnRNP) A1 splicing factor, promoting glycolytic gene expression and conferring significantly shorter survival in patients. HnRNPA1 promotes splicing of a transcript encoding the Myc-interacting partner Max, generating Delta Max, an enhancer of Myc-dependent transformation. Delta Max, but not full-length Max, rescues Myc-dependent glycolytic gene expression upon induced EGFRvIII loss, and correlates with hnRNPA1 expression and downstream Myc-dependent gene transcription in patients. Finally, Delta Max is shown to promote glioma cell proliferation in vitro and augment EGFRvIII expressing GBM growth in vivo. These results demonstrate an important role for alternative splicing in GBM and identify Delta Max as a mediator of Myc-dependent tumor cell metabolism.

引用

页码：1000 / 1008

页数：9

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