Inhibition of KDM4A Enzyme Slows Growth and Spread of Head and Neck Cancers

Inhibition of KDM4A Enzyme Slows Growth and Spread of Head and Neck Cancers

Image Source: UCLA School of Dentistry

Researchers at the UCLA School of Dentistry have shown it is possible to significantly slow the growth and spread of head and neck tumors in mice by targeting an enzyme known as KDM4A. KDM4A is an epigenetic factor – a molecule that regulates gene expression either by silencing or activating genes. KDM4A is overexpressed in the squamous cells of head and neck cancers, and the genes activated by the enzyme are associated with cancer cell replication and metastasis.

While many cancers can be treated with immunotherapy, squamous cell carcinomas in the head and neck do not respond well to this therapy and become resistant to treatment, so new methods of treatments are needed. The prognosis for individuals diagnosed with head and neck cancers is generally poor, with a high 5-year mortality rate.

“We know that the KDM4A gene plays a critical role in cancer cell replication and spread, so we focused our study on removing this gene to see if we would get an opposite response,” said professor Dr. Cun-Yu Wang, chair of oral biology at the dentistry school, who led the study.

The researchers removed the KDM4A gene in mice and found that there was a notable decrease in squamous cell carcinomas and much lower metastasis to the lymph nodes. When KDM4A was removed, the researchers found there was recruitment and activation of T cells, which killed cancer cells and stimulated inherent tumor immunity.

Further studies on why squamous carcinoma cells responded poorly to immunotherapy showed that removal of KDM4A and use of a PD-1 blockade to signal to immunotherapy drugs to attack cancer cells further decreased squamous cell cancer growth and lymph node metastasis. The efficacy of the original PD-1 blockade–based immunotherapy was further improved with the use of a small-molecule inhibitor of KDM4A. This inhibitor also helped remove cancer stem cells, which usually lead to relapse after treatment.

“Our results demonstrate that targeting KDM4A can activate anti-tumor immunity and enable PD1 blockade immunotherapy by aggravating replication stress in squamous cell carcinoma cells,” explained the researchers.

Further studies to identify more specific inhibitors of KDM4A could pave the way to the development of more effective immunotherapies for cancers of the head and neck.

You can read more about the study in the paper –Targeting KDM4A epigenetically activates tumor-cell-intrinsic immunity by inducing DNA replication stress – which was recently published in Molecular Cell. DOI: 10.1016/j.molcel.2021.02.038