A cytoplasmic COMPASS is necessary for cell survival and triple-negative breast cancer pathogenesis by regulating metabolism
- Lu Wang1,
- Clayton K. Collings1,
- Zibo Zhao1,
- Kira Alia Cozzolino1,2,
- Quanhong Ma3,
- Kaiwei Liang1,
- Stacy A. Marshall1,
- Christie C. Sze1,
- Rintaro Hashizume2,
- Jeffrey Nicholas Savas2 and
- Ali Shilatifard1,4
- 1Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA;
- 2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA;
- 3Department of Neurosurgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA;
- 4Robert H. Lurie National Cancer Institute Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
- Corresponding author: ash{at}northwestern.edu
Abstract
Mutations and translocations within the COMPASS (complex of proteins associated with Set1) family of histone lysine methyltransferases are associated with a large number of human diseases, including cancer. Here we report that SET1B/COMPASS, which is essential for cell survival, surprisingly has a cytoplasmic variant. SET1B, but not its SET domain, is critical for maintaining cell viability, indicating a novel catalytic-independent role of SET1B/COMPASS. Loss of SET1B or its unique cytoplasmic-interacting protein, BOD1, leads to up-regulation of expression of numerous genes modulating fatty acid metabolism, including ADIPOR1 (adiponectin receptor 1), COX7C, SDC4, and COQ7. Our detailed molecular studies identify ADIPOR1 signaling, which is inactivated in both obesity and human cancers, as a key target of SET1B/COMPASS. Collectively, our study reveals a cytoplasmic function for a member of the COMPASS family, which could be harnessed for therapeutic regulation of signaling in human diseases, including cancer.
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.306092.117.
- Received August 16, 2017.
- Accepted October 23, 2017.
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