HDACs as an emerging target in endocrine tumors: a comprehensive review

ABSTRACT

Introduction

The pathogenic role of deregulated histone (de-)acetylation by histone deacetyles (HDACs) has been demonstrated in several human cancers. While some HDAC inhibitors (HDACi) have been approved for individual entities, for endocrine tumors such translation into clinical practice has not yet been achieved.

Areas covered

Relevant results identified by structured searches in PubMed as well as in reference lists are summarized in a narrative review to discuss the current knowledge of HDAC involvement and their therapeutic relevance in endocrine tumors. For thyroid, neuroendocrine, and adrenal tumors, various oncogenic mechanisms of HDAC deregulation and effects of HDAC inhibitors (HDACi) have been identified in preclinical studies including direct cancer cell toxicity and modification of differentiation status.

Expert opinion

Based on positive pre-clinical results, the research on HDAC (inhibition) in the various endocrine tumors should be intensified – yet, it needs to be considered that i) HDACs’ oncogenic actions might constitute only a part of epigenetic mechanisms driving cancer, ii) individual HDAC has different roles in different endocrine tumor entities, iii) inhibition of HDACs might be especially attractive in combination with conventional or other targeted therapies, and iv) new HDAC-inhibiting drugs with improved specificity or functionally modified HDACi might further improve their efficacy.

KEYWORDS:

• Histone deacetylase
• HDAC inhibitor
• endocrine tumors
• thyroid cancer
• neuroendocrine tumor
• adrenal cancer

Article highlights

• Histone deacetylases (HDACs) are essentially involved in the human carcinogenesis via different ways of actions promoting the ’hallmarks‘ of cancer.

• (Neuro-)endocrine tumors exhibit heterogeneous expression pattern of HDACs, which could be successfully targeted by pan- and selective HDAC inhibitors (HDACi) in vitro and in vivo.

• Besides inhibition of proliferation and induction of apoptosis, treatment of (neuro-)endocrine tumors with HDACi can lead to re-differentiation of de-differentiated tumor cells. Along with the associated re-activation of silenced genes, additional targets for specific/targeted therapies might emerge.

• HDACi can improve the efficacy of standard chemotherapy and small molecules in a combinatory treatment for (neuro-)endocrine tumors.

• As most of our knowledge of HDACi in (neuro-)endocrine tumors based on in vitro and in vivo data, translation of HDACi-based mono- and combinatory therapies to clinical management of (neuro-)endocrine tumors is currently missing.

Declaration of interest

D. Neureiter has received honoraria for advisory role from Boehringer Ingelheim Pharma GmbH & Co and Lilly Austria.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.