Histone deacetylase 6 in cancer

Abstract

Histone acetylation and deacetylation are important epigenetic mechanisms that regulate gene expression and transcription. Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family that not only participates in histone acetylation and deacetylation but also targets several nonhistone substrates, such as α-tubulin, cortactin, and heat shock protein 90 (HSP90), to regulate cell proliferation, metastasis, invasion, and mitosis in tumors. Furthermore, HDAC6 also upregulates several critical factors in the immune system, such as program death receptor-1 (PD-1) and program death receptor ligand-1 (PD-L1) receptor, which are the main targets for cancer immunotherapy. Several selective HDAC6 inhibitors are currently in clinical trials for cancer treatment and bring hope for patients with malignant tumors. A fuller understanding of HDAC6 as a critical regulator of many cellular pathways will help further the development of targeted anti-HDAC6 therapies. Here, we review the unique features of HDAC6 and its role in cancer, which make HDAC6 an appealing drug target.

Radiosynthesis and preliminary evaluation of an18F‐labeled tubastatin A analog for PET imaging of histone deacetylase 6

“…Murine testis is known to exhibit high expression levels of HDAC6. 23,54 At the late time points in the biodistribution assay, the radioactivity levels of blood and muscle of [ 18 F]3-injected mice were comparable with those of [ 11 C]2-injected mice, which demonstrated specific uptake to B16F10 melanoma cells grafted in mice with a tumor/muscle ratio of approximately 3 in a small animal PET study. 49 In our study, however, testis radioactivity was below blood levels at every time point for both [ 11 C]2 and [ 18 F]3.…”

“…17,53 Furthermore, HDAC6-selective inhibitors have been evaluated in preclinical and clinical trials against cancers such as glioblastoma, multiple myeloma, and malignant melanoma. 23,54 At the late time points in the biodistribution assay, the radioactivity levels of blood and muscle of [ 18 F]3-injected mice were comparable with those of [ 11 C]2-injected mice, which demonstrated specific uptake to B16F10 melanoma cells grafted in mice with a tumor/muscle ratio of approximately 3 in a small animal PET study. 39 Therefore, use of [ 18 F]3 for PET imaging of these cancers is justified.…”

“…16,17 Additionally, HDAC6 has an ubiquitin binding domain and is involved in the degradation of misfolded and ubiquitinated proteins. 23 In the past decade, a number of radiolabeled HDAC ligands for positron emission tomography (PET) imaging have been developed. 20,21 These characteristics of HDAC6 have spurred interest in targeting it with therapeutics for cancers and neurodegenerative diseases, 14,22 with several clinical trials of selective HDAC6 inhibitors for cancers having been performed.…”

“…20,21 These characteristics of HDAC6 have spurred interest in targeting it with therapeutics for cancers and neurodegenerative diseases, 14,22 with several clinical trials of selective HDAC6 inhibitors for cancers having been performed. 23 In the past decade, a number of radiolabeled HDAC ligands for positron emission tomography (PET) imaging have been developed. [24][25][26] Besides the detection of regions with abnormalities in HDAC expression levels, PET imaging can contribute to the development of HDAC inhibitor drugs by enabling the assessment of target engagement.…”

A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin

“…12E, Table 3 ). HDAC6 has a unique structure among histone deacetylases, increasing the ability to target it pharmacologically [232]. A clinical trial using Vorinostat in combination with paclitaxel and doxorubicin-cyclophosphamide to treat advanced breast cancer showed a positive response and reduced expression of HDAC6 in the primary tumor [233].…”