title: Amplification of USP13 drives ovarian cancer metabolism.
abstract: Dysregulated energetic metabolism has been recently identified as a hallmark of cancer. Although mutations in metabolic enzymes hardwire metabolism to tumourigenesis, they are relatively infrequent in ovarian cancer. More often, cancer metabolism is re-engineered by altered abundance and activity of the metabolic enzymes. Here we identify ubiquitin-specific peptidase 13 (USP13) as a master regulator that drives ovarian cancer metabolism. USP13 specifically deubiquitinates and thus upregulates ATP citrate lyase and oxoglutarate dehydrogenase, two key enzymes that determine mitochondrial respiration, glutaminolysis and fatty acid synthesis. The USP13 gene is co-amplified with PIK3CA in 29.3% of high-grade serous ovarian cancers and its overexpression is significantly associated with poor clinical outcome. Inhibiting USP13 remarkably suppresses ovarian tumour progression and sensitizes tumour cells to the treatment of PI3K/AKT inhibitor. Our results reveal an important metabolism-centric role of USP13, which may lead to potential therapeutics targeting USP13 in ovarian cancers.
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Cecil
authors.identifier: http://orcid.org/0000-0001-9200-7207
authors.initials: C
authors.lastname: Han
authors.affiliation: Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas 77005, USA.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Hyun Ho
authors.initials: HH
authors.lastname: Choi
authors.affiliation: Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas 77005, USA.
authors.forename: Joelle
authors.initials: J
authors.lastname: Baddour
authors.affiliation: Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas 77005, USA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Achreja
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha 410008, China.
authors.forename: Jiada
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Guohui
authors.initials: G
authors.lastname: Wan
authors.affiliation: Drug Discovery Laboratory, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Ji
authors.affiliation: Department of Gynaecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Xinna
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas 77005, USA.|Department of Bioengineering, Rice University, Houston, Texas 77005, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Nagrath
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Xiongbin
authors.initials: X
authors.lastname: Lu
mesh_terms: D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D055785:Gene Knockdown Techniques; D015894:Genome, Human; D005973:Glutamine / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008055:Lipids / Q000096:biosynthesis; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D008055:Lipids; D047428:Protein Kinase Inhibitors; D005973:Glutamine; D051057:Proto-Oncogene Proteins c-akt; D010450:Endopeptidases; C561638:USP13 protein, human; D064570:Ubiquitin-Specific Proteases