TY - JOUR
T1 - Transcription factor NKX2–1 drives serine and glycine synthesis addiction in cancer
AU - Heylen, Elien
AU - Verstraete, Paulien
AU - van Aerschot, Linde
AU - Geeraerts, Shauni L.
AU - Venken, Tom
AU - Timcheva, Kalina
AU - Nittner, David
AU - Verbeeck, Jelle
AU - Royaert, Jonathan
AU - Gijbels, Marion
AU - Uyttebroeck, Anne
AU - Segers, Heidi
AU - Lambrechts, Diether
AU - Cools, Jan
AU - de Keersmaecker, Kim
AU - Kampen, Kim R.
N1 - Funding Information: This research was funded by Stichting tegen kanker (project F/2020/1333), Fonds Wetenschappelijk Onderzoek (FWO) (G0A4220N), KU Leuven (C14/18/104) and Kom op tegen Kanker (Stand up to Cancer), the Flemish cancer society (project ID: 13035). EH received an FWO PhD fellowship fundamental research (1106121 N). SLG received an SB PhD fellowship from FWO (1S14517N). PV is supported by an FWO PhD fellowship fundamental research (1116822N). KRK was funded by a research grant from FWO (FWO KAN2018 1501419 N), the young investigator grant from KWF (project ID:13486), and the FEBS excellence award 2021. Publisher Copyright: © 2023, The Author(s).
PY - 2023/5/11
Y1 - 2023/5/11
N2 - 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.].
AB - 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.].
UR - http://www.scopus.com/inward/record.url?scp=85150157250&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41416-023-02216-y
DO - https://doi.org/10.1038/s41416-023-02216-y
M3 - Article
C2 - 36932191
SN - 0007-0920
VL - 128
SP - 1862
EP - 1878
JO - British journal of cancer
JF - British journal of cancer
IS - 10
ER -