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.
How this study connects
Role on claims
Each row is a claim on a concept or method page where this paper supports, challenges, or qualifies the statement. Roles are hand-checked — not a model guess.
The chain runs mutation to metabolism to chromatin mark to phenotype, each step measured.
A driver mutation raised a lactate-derived histone mark, and the mark predicted outcome. KRAS-mutant colorectal tumours showed higher H3K9 lactylation, high H3K9la predicted worse survival, and mutant KRAS induced GRAMD1A to promote cholesterol metabolism, growth and metastasis.
Evidence for the claim as stated.
The genotype-specific response is what elevates this above a correlation with the mark.
Blocking the mark reduced tumour growth in patient-derived models. Inhibiting H3K9 lactylation or GRAMD1A cut growth in patient-derived xenografts, with a larger effect in KRAS-mutant tumours.
Evidence for the claim as stated.
These marks are studied in systems that answer different questions. The cancer work links lactylation to outcome and to treatment response in patient-derived models, while the monoaminylation work establishes enzymology and rhythmicity in brain without an outcome — so the strength of evidence for the mark mattering differs by field rather than by mark.
Evidence for the claim as stated.
Open questions
Tensions this paper is part of
From concept pages' “where studies disagree.” Disagreement means the same question; scope means different assays, populations, or outcomes.
These marks are studied in systems that answer different questions. The cancer work links lactylation to outcome and to treatment response in patient-derived models, while the monoaminylation work establishes enzymology and rhythmicity in brain without an outcome — so the strength of evidence for the mark mattering differs by field rather than by mark.
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
Structured fields used in claim comparison tables when every cited study has a complete layer.
Inspect source passages
How does mutant KRAS rewrite CRC chromatin with lactate?
These passages occur verbatim in the stored paper text. They support the points listed below; they do not verify every statement in the explanation.
KRAS is mutated in approximately 40% of CRC patients.
The KRAS oncogene is mutated in approximately 40% of CRC patients
Immunofluorescence used 130 CRC tissues and 37 normal colon tissues.
we performed immunofluorescence staining on 130 CRC tissues and 37 normal colon tissues from patients
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.
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