Department of Surgery, St Jude Children’s Research Hospital, Memphis, United States
Kevin Freeman
Genetics, Genomics & Informatics, The University of Tennessee Health Science Center (UTHSC), Memphis, United States
Junmin Peng
Department of Structural Biology, St Jude Children’s Research Hospital, Memphis, United States
Andrew M Davidoff
Department of Surgery, St Jude Children’s Research Hospital, Memphis, United States; St Jude Graduate School of Biomedical Sciences, St Jude Children’s Research Hospital, Memphis, United States; Department of Pathology and Laboratory Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, United States
Gang Wu
Center for Applied Bioinformatics, St Jude Children’s Research Hospital, Memphis, United States
Department of Surgery, St Jude Children’s Research Hospital, Memphis, United States; St Jude Graduate School of Biomedical Sciences, St Jude Children’s Research Hospital, Memphis, United States; Department of Pathology and Laboratory Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, United States; College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, United States
Dysregulated pre-mRNA splicing and metabolism are two hallmarks of MYC-driven cancers. Pharmacological inhibition of both processes has been extensively investigated as potential therapeutic avenues in preclinical and clinical studies. However, how pre-mRNA splicing and metabolism are orchestrated in response to oncogenic stress and therapies is poorly understood. Here, we demonstrate that jumonji domain containing 6, arginine demethylase, and lysine hydroxylase, JMJD6, acts as a hub connecting splicing and metabolism in MYC-driven human neuroblastoma. JMJD6 cooperates with MYC in cellular transformation of murine neural crest cells by physically interacting with RNA binding proteins involved in pre-mRNA splicing and protein homeostasis. Notably, JMJD6 controls the alternative splicing of two isoforms of glutaminase (GLS), namely kidney-type glutaminase (KGA) and glutaminase C (GAC), which are rate-limiting enzymes of glutaminolysis in the central carbon metabolism in neuroblastoma. Further, we show that JMJD6 is correlated with the anti-cancer activity of indisulam, a ‘molecular glue’ that degrades splicing factor RBM39, which complexes with JMJD6. The indisulam-mediated cancer cell killing is at least partly dependent on the glutamine-related metabolic pathway mediated by JMJD6. Our findings reveal a cancer-promoting metabolic program is associated with alternative pre-mRNA splicing through JMJD6, providing a rationale to target JMJD6 as a therapeutic avenue for treating MYC-driven cancers.
