Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing associated with therapeutic response to splicing inhibitor
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 i...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2024-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/90993 |
| _version_ | 1797260747149934592 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Carolyn M Jablonowski |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T23:30:14Z |
| format | Article |
| id | doaj.art-56c3296c6a1943a796dba4f0a49cdf21 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-24T23:30:14Z |
| publishDate | 2024-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-56c3296c6a1943a796dba4f0a49cdf212024-03-15T15:28:28ZengeLife Sciences Publications LtdeLife2050-084X2024-03-011210.7554/eLife.90993Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing associated with therapeutic response to splicing inhibitorCarolyn M Jablonowski0Waise Quarni1Shivendra Singh2Haiyan Tan3Dhanushka Hewa Bostanthirige4Hongjian Jin5Jie Fang6Ti-Cheng Chang7David Finkelstein8Ji-Hoon Cho9Dongli Hu10Vishwajeeth Pagala11Sadie Miki Sakurada12Shondra M Pruett-Miller13https://orcid.org/0000-0002-3793-585XRuoning Wang14https://orcid.org/0000-0001-9798-8032Andrew Murphy15https://orcid.org/0000-0001-6747-0355Kevin Freeman16Junmin Peng17Andrew M Davidoff18Gang Wu19Jun Yang20https://orcid.org/0000-0002-4233-3220Department of Surgery, St Jude Children’s Research Hospital, Memphis, United StatesDepartment of Surgery, St Jude Children’s Research Hospital, Memphis, United StatesDepartment of Surgery, St Jude Children’s Research Hospital, Memphis, United StatesCenter for Proteomics and Metabolomics, St Jude Children's Research Hospital, Memphis, United StatesDepartment of Surgery, St Jude Children’s Research Hospital, Memphis, United StatesCenter for Applied Bioinformatics, St Jude Children’s Research Hospital, Memphis, United StatesDepartment of Surgery, St Jude Children’s Research Hospital, Memphis, United StatesCenter for Applied Bioinformatics, St Jude Children’s Research Hospital, Memphis, United StatesCenter for Applied Bioinformatics, St Jude Children’s Research Hospital, Memphis, United StatesCenter for Proteomics and Metabolomics, St Jude Children's Research Hospital, Memphis, United StatesDepartment of Surgery, St Jude Children’s Research Hospital, Memphis, United StatesCenter for Proteomics and Metabolomics, St Jude Children's Research Hospital, Memphis, United StatesDepartment of Cell and Molecular Biology, St Jude Children's Research Hospital, Memphis, United StatesDepartment of Cell and Molecular Biology, St Jude Children's Research Hospital, Memphis, United StatesCenter for Childhood Cancer and Blood Disease, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, United StatesDepartment of Surgery, St Jude Children’s Research Hospital, Memphis, United StatesGenetics, Genomics & Informatics, The University of Tennessee Health Science Center (UTHSC), Memphis, United StatesDepartment of Structural Biology, St Jude Children’s Research Hospital, Memphis, United StatesDepartment 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 StatesCenter for Applied Bioinformatics, St Jude Children’s Research Hospital, Memphis, United StatesDepartment 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 StatesDysregulated 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.https://elifesciences.org/articles/90993JMJD6GLSneuroblastomasplicingindisulam |
| spellingShingle | 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 Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing associated with therapeutic response to splicing inhibitor eLife JMJD6 GLS neuroblastoma splicing indisulam |
| title | Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing associated with therapeutic response to splicing inhibitor |
| title_full | Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing associated with therapeutic response to splicing inhibitor |
| title_fullStr | Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing associated with therapeutic response to splicing inhibitor |
| title_full_unstemmed | Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing associated with therapeutic response to splicing inhibitor |
| title_short | Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing associated with therapeutic response to splicing inhibitor |
| title_sort | metabolic reprogramming of cancer cells by jmjd6 mediated pre mrna splicing associated with therapeutic response to splicing inhibitor |
| topic | JMJD6 GLS neuroblastoma splicing indisulam |
| url | https://elifesciences.org/articles/90993 |
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