Inhibition of histone deacetylases attenuates tumor progression and improves immunotherapy in breast cancer

by Selleckchem | Oct 29 2023

Breast cancer is one of the common malignancies with poor prognosis worldwide. The treatment of breast cancer patients includes surgery, radiation, hormone therapy, chemotherapy, targeted drug therapy and immunotherapy. In recent years, immunotherapy has potentiated the survival of certain breast cancer patients; however, primary resistance or acquired resistance attenuate the therapeutic outcomes. Histone acetyltransferases induce histone acetylation on lysine residues, which can be reversed by histone deacetylases (HDACs). Dysregulation of HDACs via mutation and abnormal expression contributes to tumorigenesis and tumor progression. Numerous HDAC inhibitors have been developed and exhibited the potent anti-tumor activity in a variety of cancers, including breast cancer. HDAC inhibitors ameliorated immunotherapeutic efficacy in cancer patients. In this review, we discuss the anti-tumor activity of HDAC inhibitors in breast cancer, including dacinostat, belinostat, abexinostat, mocetinotat, panobinostat, romidepsin, entinostat, vorinostat, pracinostat, tubastatin A, trichostatin A, and tucidinostat. Moreover, we uncover the mechanisms of HDAC inhibitors in improving immunotherapy in breast cancer. Furthermore, we highlight that HDAC inhibitors might be potent agents to potentiate immunotherapy in breast cancer.

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Breast cancer is a common and aggressive form of cancer that has a poor prognosis. Current treatment options for breast cancer include surgery, radiation, hormone therapy, chemotherapy, targeted drug therapy, and immunotherapy. Immunotherapy has shown promising results in improving the survival of certain breast cancer patients. However, some patients either do not respond to immunotherapy initially (primary resistance) or develop resistance over time (acquired resistance), limiting the effectiveness of this treatment approach.

Histone acetyltransferases (HATs) are enzymes that add acetyl groups to lysine residues on histone proteins, leading to a more relaxed chromatin structure and increased gene expression. On the other hand, histone deacetylases (HDACs) remove acetyl groups from histones, resulting in a more condensed chromatin structure and decreased gene expression. Dysregulation of HDACs through genetic mutations or abnormal expression has been implicated in the development and progression of various cancers, including breast cancer.

In recent years, several HDAC inhibitors have been developed and shown to have potent anti-tumor activity in various cancer types, including breast cancer. Some of the HDAC inhibitors that have been studied in breast cancer include dacinostat, belinostat, abexinostat, mocetinostat, panobinostat, romidepsin, entinostat, vorinostat, pracinostat, tubastatin A, trichostatin A, and tucidinostat. These inhibitors work by blocking the activity of HDACs, leading to increased histone acetylation and subsequent changes in gene expression that can inhibit tumor growth and promote cell death.

Importantly, HDAC inhibitors have also been found to enhance the efficacy of immunotherapy in breast cancer. The mechanisms underlying this effect include the modulation of immune checkpoint molecules, such as PD-L1, on tumor cells, leading to increased recognition and killing of cancer cells by immune cells. HDAC inhibitors can also promote the infiltration of immune cells into the tumor microenvironment and enhance their anti-tumor activity. Additionally, HDAC inhibitors have been shown to increase the expression of tumor antigens, making cancer cells more susceptible to immune recognition and destruction.

Overall, the use of HDAC inhibitors in breast cancer has shown promise in preclinical and clinical studies. These agents not only exhibit direct anti-tumor effects but also have the potential to enhance the effectiveness of immunotherapy. Further research is needed to fully understand the mechanisms of action and optimal combination strategies involving HDAC inhibitors and immunotherapy in breast cancer treatment.