Dataset Information
Transcription factor NKX2-1 drives serine and glycine synthesis addiction in cancer.
Ontology highlight
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.
SUBMITTER: Heylen E
PROVIDER: S-EPMC10147615 | biostudies-literature | 2023 May
REPOSITORIES: biostudies-literature
Publications
Transcription factor NKX2-1 drives serine and glycine synthesis addiction in cancer.
British journal of cancer 20230317 10
<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]
