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

• Published in: British journal of cancer 2023-05, Vol.128 (10), p.1862-1878
• Main Authors: Heylen, Elien, Verstraete, Paulien, Van Aerschot, Linde, Geeraerts, Shauni L., Venken, Tom, Timcheva, Kalina, Nittner, David, Verbeeck, Jelle, Royaert, Jonathan, Gijbels, Marion, Uyttebroeck, Anne, Segers, Heidi, Lambrechts, Diether, Cools, Jan, De Keersmaecker, Kim, Kampen, Kim R.
• Format: Article
• Language: English
• Subjects: 631/67/1059/602; 631/67/1612/1350; 631/67/1990/283/2125; 631/67/2327; 631/67/395; Addictions; Animal models; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell culture; Cell Line; Cell Line, Tumor; Chemotherapy; Drug Resistance; Epidemiology; Etoposide; Glycine; Humans; Immunoblotting; Leukemia; Lung cancer; Lung Neoplasms - pathology; Lymphocytes T; Mass spectroscopy; Metabolism; Mice; Molecular Medicine; Nucleotides; Oncology; Prostate cancer; Serine; Serine - metabolism; Sertraline; Thyroid Nuclear Factor 1 - metabolism; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-023-02216-y

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.