SQSTM1 is a pathogenic target of 5q copy number gains in kidney cancer

Lianjie Li; Chuan Shen; Eijiro Nakamura; Kiyohiro Ando; Sabina Signoretti; Rameen Beroukhim; Glenn S Cowley; Patrick Lizotte; Ella Liberzon; Steven Bair; David E Root; Pablo Tamayo; Aviad Tsherniak; Su-Chun Cheng; Barbara Tabak; Anders Jacobsen; A Ari Hakimi; Nikolaus Schultz; Giovanni Ciriello; Chris Sander; James J Hsieh; William G Kaelin Jr

doi:10.1016/j.ccr.2013.10.025

SQSTM1 is a pathogenic target of 5q copy number gains in kidney cancer

Cancer Cell. 2013 Dec 9;24(6):738-50. doi: 10.1016/j.ccr.2013.10.025.

Authors

Lianjie Li¹, Chuan Shen¹, Eijiro Nakamura¹, Kiyohiro Ando¹, Sabina Signoretti², Rameen Beroukhim³, Glenn S Cowley⁴, Patrick Lizotte⁴, Ella Liberzon⁵, Steven Bair¹, David E Root⁴, Pablo Tamayo⁴, Aviad Tsherniak⁴, Su-Chun Cheng⁶, Barbara Tabak⁷, Anders Jacobsen⁸, A Ari Hakimi⁹, Nikolaus Schultz⁸, Giovanni Ciriello⁸, Chris Sander⁸, James J Hsieh¹⁰, William G Kaelin Jr¹¹

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁴ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
⁶ Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
⁷ Department of Cancer Biology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁸ Department of Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 16605, USA.
⁹ Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 16605, USA.
¹⁰ Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 16605, USA; Department of Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 16605, USA.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: william_kaelin@dfci.harvard.edu.

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer and is often linked to loss of chromosome 3p, which harbors the VHL tumor suppressor gene, loss of chromosome 14q, which includes HIF1A, and gain of chromosome 5q. The relevant target(s) on chromosome 5q is not known. Here, we show that 5q amplification leads to overexpression of the SQSTM1 oncogene in ccRCC lines and tumors. Overexpression of SQSTM1 in ccRCC lines promoted resistance to redox stress and increased soft agar growth, while downregulation of SQSTM1 decreased resistance to redox stress, impaired cellular fitness, and decreased tumor formation. Therefore, the selection pressure to amplify 5q in ccRCC is driven, at least partly, by SQSTM1.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics*
Adaptor Proteins, Signal Transducing / physiology
Animals
Base Sequence
Carcinoma, Renal Cell / genetics*
Cell Line, Tumor
Chromosomes, Human, Pair 5*
Gene Dosage*
Humans
Kidney Neoplasms / genetics*
Mice
Molecular Sequence Data
NF-E2-Related Factor 2 / analysis
NF-E2-Related Factor 2 / physiology
Sequestosome-1 Protein

Substances

Adaptor Proteins, Signal Transducing
NF-E2-Related Factor 2
NFE2L2 protein, human
SQSTM1 protein, human
Sequestosome-1 Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding