A research team led by Professor Chan Kui-ming from the Department of Biomedical Sciences at CityUHK, discovered that H2BE113K, a missense H2B mutation, promotes colony formation and lung metastasis of breast cancer.

A research team led by Professor Chan Kui-ming from the Department of Biomedical Sciences at CityUHK, discovered that H2BE113K, a missense H2B mutation, promotes colony formation and lung metastasis of breast cancer. The research revealed that H2BE113K plays a critical role in chromatin regulation, cellular function and breast cancer progression, shedding lights on novel targeted therapy of breast cancer.

Recent research primarily investigated the effect of multiple H3 mutations to tumorigenesis, yet a significant number of H2B histone mutations were identified in cancer patients. Professor Chan and his team has previously identified the vital roles of H2BG53D and H2BE76K mutations in pancreatic cancer and breast cancer. This study focuses on H2BE113K, a histone H2B mutation identified predominantly in breast and lung cancers, and was published in Science Advances, titled “H2BE113K mutation promotes breast cancer metastasis through modulating chromatin dynamics”.

The research team used CRISPR-Cas9 approach to generate H2BE113K knock-in breast cancer cells, revealing that this histone mutation has no effect on cell proliferation and cell migration, yet it significantly enhanced colony formation ability of breast cancer cells. The team then performed RNA sequencing and CUT & RUN sequencing, successfully identifying 221 candidate genes affected by H2BE113K, and some of these genes have been implicated in various cancers, including RAD50 and G3BP2.

The research discovered that H2BE113K would recruit SMARCA5, a chromatin remodelling protein to the G3BP2 promoter region, which up-regulated G3BP2 expression and enhanced colony formation ability of breast cancer cells. The team investigated both human breast cancer cells and gene-edited mice and proved that H2BE113K did not affect the development and growth of tumours but promote lung metastasis of breast cancer. As cancer metastasis is the major cause of cancer mortality, these findings are important for breast cancer treatment.

Importantly, the research also indicated that ED2-AD101, a first-in-class SMARCA5 inhibitor, effectively diminished the excessive colony formation observed in H2BE113K mutant cells, implying that inhibiting the activity of SMARCA5 promises a new direction in relevant cancer therapy.

Professor Chan noted, “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.”

CityUHK has established several new academic institutes and colleges in recent years, including the College of Biomedicine, to further strengthen its research and innovation ecosystem. The College of Biomedicine comprises the Department of Biomedical Engineering, the Department of Biomedical Sciences, and the Department of Neuroscience. It aims to tackle pressing challenges in the life and health sciences through interdisciplinary collaboration.