STAR RNA-binding protein Quaking suppresses cancer via stabilization of specific miRNA
- An-Jou Chen1,2,3,
- Ji-Hye Paik1,2,3,
- Hailei Zhang1,2,
- Sachet A. Shukla1,2,
- Richard Mortensen4,
- Jian Hu1,2,3,5,
- Haoqiang Ying1,2,3,5,
- Baoli Hu1,2,5,
- Jessica Hurt6,
- Natalie Farny6,
- Caroline Dong1,2,
- Yonghong Xiao1,2,
- Y. Alan Wang1,2,5,
- Pamela A. Silver6,
- Lynda Chin1,2,5,7,
- Shobha Vasudevan4 and
- Ronald A. DePinho1,2,3,8,9
- 1Belfer Institute for Applied Cancer Science,
- 2Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 3Department of Medicine and Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 4Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA;
- 5Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
- 6Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 7Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 8Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
Abstract
Multidimensional cancer genome analysis and validation has defined Quaking (QKI), a member of the signal transduction and activation of RNA (STAR) family of RNA-binding proteins, as a novel glioblastoma multiforme (GBM) tumor suppressor. Here, we establish that p53 directly regulates QKI gene expression, and QKI protein associates with and leads to the stabilization of miR-20a; miR-20a, in turn, regulates TGFβR2 and the TGFβ signaling network. This pathway circuitry is substantiated by in silico epistasis analysis of its components in the human GBM TCGA (The Cancer Genome Atlas Project) collection and by their gain- and loss-of-function interactions in in vitro and in vivo complementation studies. This p53–QKI–miR-20a–TGFβ pathway expands our understanding of the p53 tumor suppression network in cancer and reveals a novel tumor suppression mechanism involving regulation of specific cancer-relevant microRNAs.
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Footnotes
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↵9 Corresponding author
E-mail rdepinho{at}mdanderson.org
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.189001.112.
- Received February 4, 2012.
- Accepted May 24, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press