Epigenetics
How does mutant KRAS rewrite CRC chromatin with lactate?
Open access · cc by · source: Europe PMC
In KRAS-mutant colorectal cancer, extra lactate boosts H3K9 lactylation, which opens chromatin at GRAMD1A and fuels cholesterol-driven growth; blocking H3K9la or GRAMD1A shrinks PDX tumors.
Study at a glance
- Design
- Animal / in-vitro — KRAS-mutant vs wild-type CRC tissues, cell lines, ChIP/RNA-seq, and PDX mice testing H3K9la–GRAMD1A–cholesterol signaling
- N
- N=167 · Immunofluorescence on 130 CRC and 37 normal colon tissues; plus cell lines, TCGA, and KRAS-mutant/wild-type PDX models
- Population
- Human colorectal tumors and matched normals, CRC cell lines, TCGA transcriptomes, and CRC patient-derived xenograft mice
- Outcome
- H3K9la/lactylation levels, GRAMD1A expression, cholesterol metabolism, proliferation/migration, survival, and PDX tumor growth
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Key findings
KRAS-mutant tumors had higher lactate-driven H3K9la; high H3K9la predicted worse survival. Mutant KRAS induced GRAMD1A, promoting cholesterol metabolism, growth, and metastasis. Inhibiting H3K9la or GRAMD1A cut PDX growth, more so in KRAS-mutant PDX.
Methodology
Compared lactylation/H3K9la in 130 CRC vs 37 normal tissues and KRAS-mutant vs wild-type cells, linked levels to stage/survival, traced GRAMD1A via H3K9la chromatin accessibility, and treated KRAS-mutant and wild-type PDX mice with LDH or GRAMD1A inhibitors.
Limitations
Tissue associations and PDX responses do not prove a ready human drug; KRAS is mutated in ~40% of CRC so wild-type tumors may respond less, and cholesterol effects were not a randomized clinical trial.
How this study connects
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