Transcription factor NKX2–1 drives serine and glycine synthesis addiction in cancer

Elien Heylen, Paulien Verstraete, Linde van Aerschot, Shauni L. Geeraerts, Tom Venken, Kalina Timcheva, David Nittner, Jelle Verbeeck, Jonathan Royaert, Marion Gijbels, Anne Uyttebroeck, Heidi Segers, Diether Lambrechts, Jan Cools, Kim de Keersmaecker, Kim R. Kampen

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Scopus)

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. [Figure not available: see fulltext.].
Original languageEnglish
Pages (from-to)1862-1878
Number of pages17
JournalBritish journal of cancer
Volume128
Issue number10
DOIs
Publication statusPublished - 11 May 2023
Externally publishedYes

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