Impaired Histone Inheritance Increases Breast Cancer Growth

Chromatin states and the epigenetic information associated with them are critical in sustaining cell identity when it divides. Histone post-translational modifications (PTMs) are critical determinants of cellular epigenetic status, transporting epigenetic information and controlling gene transcription. Epigenetic changes have been related to a variety of disorders, including breast cancer. However, it is unknown what function parental histone inheritance has in carcinogenesis or tumor evolution.

A team from the Chinese Academy of Sciences’ Shenzhen Institute of Advanced Technology (SIAT) developed a tumor model that introduces an MCM2-2A mutation, which is defective in parental histone binding, into breast cancer cell lines to investigate the impact of impaired parental histone inheritance on histone modification profiles in MCM2 mutant cells. On June 10, the work was published in Nature Communications.

The researchers found alterations in the distribution of numerous PTMs, including both repressed and active histone marks, in this model. Impaired histone inheritance led to significant epigenetic reprogramming, particularly affecting the repressive histone mark H3K27me3.

“The loss of H3K27me3 at the promoters of development-related genes resulted in their activation in cancer cells, thereby promoting tumor growth and metastasis,” said Prof. Gan Yunhai, corresponding author of the study.

Furthermore, after orthotopic transplantation, cancer cells with defective histone inheritance showed faster proliferation and a proclivity to become more aggressive. Additionally, it was identified in a study that hormonal contraceptives increase breast cancer risk.

Following that, single-cell RNA sequencing demonstrated that newly produced subclones in cancer cells with histone inheritance problems aided tumor development. When confronted with more complicated surroundings, these subclones gained advantages in proliferation and fitness, evolving faster.

This work confirms the importance of parental histone inheritance carrying H3K27me3 in the maintenance of specific areas of differentiated cells. Failure to repair H3K27me3 can reactivate mammary gland growth processes, which are frequently used by breast cancer cells as tumor progression drivers.

“These findings provide valuable insights into how epigenetic instability contributes to tumor progression, suggesting that targeting abnormal epigenetic inheritance may improve patient outcomes by preserving epigenetic stability,” said Prof. Gan.

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