Researchers at CityUHK discovered that the histone mutation H2BE113K promotes breast cancer lung metastasis by reshaping chromatin dynamics. Published in Science Advances, the study reveals how the mutation upregulates cancer-promoting genes and identifies a first-in-class inhibitor that blocks the process.
A research team led by Professor Chan Kui-ming from the Department of Biomedical Sciences at CityUHK has identified how a specific missense histone mutation drives breast cancer progression. While earlier investigations focused primarily on multiple H3 mutations in tumorigenesis, scientists noted that numerous H2B histone mutations appear in cancer patients.
The study, published in Science Advances, centers on H2BE113K. This particular histone H2B mutation is identified predominantly in breast and lung cancers. Prior work by the same research team had already established the vital roles of H2BG53D and H2BE76K mutations in pancreatic and breast cancers.
CRISPR-Cas9 Tests Show Mutation Increases Breast Cancer Colony Formation
To investigate how the mutation operates at a cellular level, the research team used the CRISPR-Cas9 approach to generate H2BE113K knock-in breast cancer cells. The experiments showed that the mutation does not alter cell proliferation or migration rates. However, it significantly increases the colony formation ability of breast cancer cells.
Further investigation through RNA sequencing and CUT & RUN sequencing revealed 221 candidate genes affected by the mutation. Among these are RAD50 and G3BP2, genes previously implicated in various cancers.
The team discovered that the mutated histone recruits SMARCA5, a chromatin remodelling protein, directly to the G3BP2 promoter region. This recruitment upregulates G3BP2 expression and drives the excessive colony formation observed in the mutant cells.
Tumor Growth Versus Lung Metastasis in Vivo
Experiments involving both human breast cancer cells and gene-edited mice demonstrated a distinct pattern in tumor behavior. The H2BE113K mutation does not affect the initial development and growth of primary tumors. Instead, it specifically promotes lung metastasis.
Because cancer metastasis remains the primary cause of cancer mortality, these findings carry significant weight for future therapeutic strategies. Professor Chan noted how the findings affect genomic regulation and disease.
“Histones are fundamental to the packaging and regulation of genomic DNA, and mutations in histone genes have been increasingly linked to human disease. We found that by a single amino acid substitution in histone H2B is sufficient to reshape chromatin regulation and promote breast cancer progression. This research confirms that H2BE113K is an oncohistone and opens new opportunities for precision medicine.”
Professor Chan Kui-ming, Department of Biomedical Sciences at CityUHK
Targeting SMARCA5 Inhibition for Precision Therapy
The study also evaluated a potential pharmacological countermeasure. Researchers tested ED2-AD101, described as a first-in-class SMARCA5 inhibitor, on the mutant cells.
The inhibitor successfully diminished the excessive colony formation driven by the H2BE113K mutation. This result points toward a promising new direction in targeted cancer therapy by focusing on chromatin remodelling mechanisms.