O-GlcNAc transferase maintains metabolic homeostasis in response to CDK9 inhibition

Aishwarya Gondane, Ninu Poulose, Suzanne Walker, Ian G Mills, Harri M Itkonen

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)
77 Downloads (Pure)

Abstract

Co-targeting of O-GlcNAc transferase (OGT) and the transcriptional kinase CDK9 is toxic to prostate cancer cells. As OGT is an essential glycosyltransferase, identifying an alternative target showing similar effects is of great interest. Here, we used a multiomics approach (transcriptomics, metabolomics and proteomics) to better understand the mechanistic basis of the combinatorial lethality between OGT and CDK9 inhibition. CDK9 inhibition preferentially affected transcription. In contrast, depletion of OGT activity predominantly remodeled the metabolome. Using an unbiased systems biology approach (weighted gene correlation network analysis), we discovered that CDK9 inhibition alters mitochondrial activity / flux, and high OGT activity is essential to maintain mitochondrial respiration when CDK9 activity is depleted. Our metabolite profiling data revealed that pantothenic acid (vitamin B5) is the metabolite that is most robustly induced by both OGT and OGT+CDK9 inhibitor treatments, but not by CDK9 inhibition alone. Finally, supplementing prostate cancer cell lines with vitamin B5 in the presence of CDK9 inhibitor mimics the effects of co-targeting OGT and CDK9.
Original languageEnglish
Pages (from-to)751–759
JournalGlycobiology
Volume32
Issue number9
Early online date16 Jun 2022
DOIs
Publication statusPublished - Sept 2022

Bibliographical note

© The Author(s) 2022. Published by Oxford University Press.

Keywords

  • Cyclin-dependent kinase 9
  • O-GlcNAc transferase
  • metabolism
  • prostate cancer
  • systems biology

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