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Transcription factor NKX2-1 drives serine and glycine synthesis addiction in cancer. | LitMetric

AI Article Synopsis

  • One-third of cancers rely on the metabolism of serine and glycine for growth and survival, driven by the transcription factor NKX2-1, which promotes the synthesis of these amino acids.
  • Researchers used various laboratory techniques and models, including cancer cell lines and mouse models, to investigate the role of NKX2-1 in metabolic rewiring and its effects on cancer proliferation and invasion.
  • The study found that NKX2-1 enhances tumor aggressiveness and suggests that targeting serine/glycine metabolism can be a promising treatment strategy for cancers driven by this transcription factor, especially using repurposed drugs like sertraline.

Article Abstract

Background: One-third of cancers activate endogenous synthesis of serine/glycine, and can become addicted to this pathway to sustain proliferation and survival. Mechanisms driving this metabolic rewiring remain largely unknown.

Methods: NKX2-1 overexpressing and NKX2-1 knockdown/knockout T-cell leukaemia and lung cancer cell line models were established to study metabolic rewiring using ChIP-qPCR, immunoblotting, mass spectrometry, and proliferation and invasion assays. Findings and therapeutic relevance were validated in mouse models and confirmed in patient datasets.

Results: Exploring T-cell leukaemia, lung cancer and neuroendocrine prostate cancer patient datasets highlighted the transcription factor NKX2-1 as putative driver of serine/glycine metabolism. We demonstrate that transcription factor NKX2-1 binds and transcriptionally upregulates serine/glycine synthesis enzyme genes, enabling NKX2-1 expressing cells to proliferate and invade in serine/glycine-depleted conditions. NKX2-1 driven serine/glycine synthesis generates nucleotides and redox molecules, and is associated with an altered cellular lipidome and methylome. Accordingly, NKX2-1 tumour-bearing mice display enhanced tumour aggressiveness associated with systemic metabolic rewiring. Therapeutically, NKX2-1-expressing cancer cells are more sensitive to serine/glycine conversion inhibition by repurposed anti-depressant sertraline, and to etoposide chemotherapy.

Conclusion: Collectively, we identify NKX2-1 as a novel transcriptional regulator of serine/glycine synthesis addiction across cancers, revealing a therapeutic vulnerability of NKX2-1-driven cancers. Transcription factor NKX2-1 fuels cancer cell proliferation and survival by hyperactivating serine/glycine synthesis, highlighting this pathway as a novel therapeutic target in NKX2-1-positive cancers.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10147615PMC
http://dx.doi.org/10.1038/s41416-023-02216-yDOI Listing

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