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Contribution of Histone Deacetylases in Prognosis and Therapeutic Management of Cholangiocarcinoma

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Abstract

Cholangiocarcinoma (CCA), a malignant tumor that occurs in the epithelium of the biliary tract, has a very poor prognosis because affected patients are frequently diagnosed at an advanced stage and recurrence after resection is common. Over the last two decades, our understanding of the molecular biology of this malignancy has expanded, and various studies have explored targeted therapy for CCA in order to improve patient survival. The histone acetylation/deacetylation equilibrium is affected in carcinogenesis, leading to altered chromatin structure and therefore changes in gene expression. Understanding the molecular identity of histone deacetylases (HDACs), their cellular interactions and potential role as anticancer agents will help us develop new therapeutic strategies for CCA-affected patients. Furthermore, HDAC inhibitors act on cellular stress response pathways and decrease cancer angiogenesis. Downregulation of pro-angiogenic genes such as vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 (HIF-1), and endothelial nitric oxide synthase (eNOS) inhibit formation of new vessels and can negatively affect the metastatic process. Finally, recent clinical trials prove that administration of both HDAC inhibitors and DNA-targeting chemotherapeutic agents, such as topoisomerase inhibitors, DNA intercalating agents, inhibitors of DNA synthesis, covalently modifying DNA agents, and ionizing radiation, maximizes the anticancer effect by increasing the cytotoxic efficiency of a variety of DNA-damaging anticancer drugs. Therefore, combination therapy of classic chemotherapeutic drugs with HDAC inhibitors can act synergistically for the patients’ benefit.

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Authors and Affiliations

  1. Fourth Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens, 1 Rimini Str, 12462, Athens, Greece

    Aikaterini Mastoraki, Leon Naar, Maria Ioannidi & Pantelis Vassiliu

  2. First Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece

    Dimitrios Schizas & Evangelos Felekouras

  3. Department of Medical Oncology, Metaxa Cancer Hospital, Athens, Greece

    Nikolaos Charalampakis

  4. Division of Surgical Oncology, Department of Surgery, James Cancer Hospital, Solove Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Diamantis Tsilimigras

  5. Third Department of Surgery, Evangelismos Hospital, Athens, Greece

    Maria Sotiropoulou

  6. Department of Surgery, Duke University Medical Center, Durham, NC, USA

    Dimitrios Moris

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  1. Aikaterini Mastoraki
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  2. Dimitrios Schizas
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Correspondence to Aikaterini Mastoraki.

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Aikaterini Mastoraki, Dimitrios Schizas, Nikolaos Charalampakis, Leon Naar, Maria Ioannidi, Diamantis Tsilimigras, Maria Sotiropoulou, Dimitrios Moris, Pantelis Vassiliu, and Evangelos Felekouras have no conflicts to report.

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Mastoraki, A., Schizas, D., Charalampakis, N. et al. Contribution of Histone Deacetylases in Prognosis and Therapeutic Management of Cholangiocarcinoma. Mol Diagn Ther 24, 175–184 (2020). https://doi.org/10.1007/s40291-020-00454-x

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