Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing associated with therapeutic response to splicing inhibitor.

Abstract

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.

• Authors: Carolyn M Jablonowski, Waise Quarni, Shivendra Singh, Haiyan Tan, Dhanushka Hewa Bostanthirige, Hongjian Jin, Jie Fang, Ti-Cheng Chang, David Finkelstein, Ji-Hoon Cho, Dongli Hu, Vishwajeeth Pagala, Sadie Miki Sakurada, Shondra M Pruett-Miller, Ruoning Wang, Andrew Murphy, Kevin Freeman, Junmin Peng, Andrew M Davidoff, Gang Wu, Jun Yang
• Journal: eLife (Elife) Vol. 12 (Mar 15 2024) ISSN: 2050-084X [Electronic] England
• PMID: 38488852 (Publication Type: Journal Article)
• Copyright: © 2023, Jablonowski, Quarni et al.

Chemical References

• N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide
• RNA Precursors
• Glutaminase
• Jumonji Domain-Containing Histone Demethylases
• JMJD6 protein, human
• Sulfonamides

Topics

• Humans
• Animals
• Mice
• RNA Precursors (genetics, metabolism)
• Glutaminase (genetics)
• Metabolic Reprogramming
• Jumonji Domain-Containing Histone Demethylases (metabolism)
• Neuroblastoma
• Sulfonamides