Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation
W. Brian Dalton, … , Josh Lauring, Ben Ho Park
W. Brian Dalton, … , Josh Lauring, Ben Ho Park
Published August 8, 2019
Citation Information: J Clin Invest. 2019;129(11):4708-4723. https://doi.org/10.1172/JCI125022.
View: Text | PDF
Research Article Metabolism Oncology

Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation

  • Text
  • PDF
Abstract

Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1MUT xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1MUT cancers.

Authors

W. Brian Dalton, Eric Helmenstine, Noel Walsh, Lukasz P. Gondek, Dhanashree S. Kelkar, Abigail Read, Rachael Natrajan, Eric S. Christenson, Barbara Roman, Samarjit Das, Liang Zhao, Robert D. Leone, Daniel Shinn, Taylor Groginski, Anil K. Madugundu, Arun Patil, Daniel J. Zabransky, Arielle Medford, Justin Lee, Alex J. Cole, Marc Rosen, Maya Thakar, Alexander Ambinder, Joshua Donaldson, Amy E. DeZern, Karen Cravero, David Chu, Rafael Madero-Marroquin, Akhilesh Pandey, Paula J. Hurley, Josh Lauring, Ben Ho Park

×

Figure 7

Cancer cells with naturally acquired SF3B1 mutation show vulnerability to serine and glycine starvation in vivo.

Options: View larger image (or click on image) Download as PowerPoint
Cancer cells with naturally acquired SF3B1 mutation show vulnerability t...
(A) HNT34 cells were subcutaneously injected into NSG mice given +SG or –SG diets, and tumor volume measurements were obtained starting at 5 weeks, with 10 biologic replicates in each group. (B) MUTZ3 cells were subcutaneously injected into NSGS mice given +SG or –SG diets and tumors were excised from euthanized animals and measured at week 4, with 4 biologic replicates in each group. ***P < 0.001, **P < 0.01, *P < 0.05 for t tests between dietary groups.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts