Role of Histone Deacetylase 6 and Histone Deacetylase 6 Inhibition in Colorectal Cancer

Abstract

Histone deacetylase 6 (HDAC6), by deacetylation of multiple substrates and association with interacting proteins, regulates many physiological processes that are involved in cancer development and invasiveness such as cell proliferation, apoptosis, motility, epithelial to mesenchymal transition, and angiogenesis. Due to its ability to remove misfolded proteins, induce autophagy, and regulate unfolded protein response, HDAC6 plays a protective role in responses to stress and enables tumor cell survival. The scope of this review is to discuss the roles of HDCA6 and its implications for the therapy of colorectal cancer (CRC). As HDAC6 is overexpressed in CRC, correlates with poor disease prognosis, and is not essential for normal mammalian development, it represents a good therapeutic target. Selective inhibition of HDAC6 impairs growth and progression without inducing major adverse events in experimental animals. In CRC, HDAC6 inhibitors have shown the potential to reduce tumor progression and enhance the therapeutic effect of other drugs. As HDAC6 is involved in the regulation of immune responses, HDAC6 inhibitors have shown the potential to improve antitumor immunity by increasing the immunogenicity of tumor cells, augmenting immune cell activity, and alleviating immunosuppression in the tumor microenvironment. Therefore, HDAC6 inhibitors may represent promising candidates to improve the effect of and overcome resistance to immunotherapy.

Inflammasomes Are Influenced by Epigenetic and Autophagy Mechanisms in Colorectal Cancer Signaling

“…HDAC6 is implicated in the processes of inflammasome assembly, priming, and activation [ 59 ]. Primarily through deacetylation and activation of the p65 subunit of NFκB, which subsequently stimulates the transcription of genes encoding NLRP3, pro-IL1β, and pro-IL18, HDAC6 facilitates priming of the NLRP3 inflammasome [ 60 ].…”

Histone Deacetylase 6 Inhibitor 5-Phenylcarbamoylpentyl Selenocyanide (SelSA) Suppresses Hepatocellular Carcinoma by Downregulating Phosphorylation of the Extracellular Signal-Regulated Kinase 1/2 Pathway

“…The activity of HDAC6 is a key determinant in tumor initiation and progression, and its transcriptional regulation is critical for its deacetylase activity . Abnormally high expression of HDAC6 has been confirmed to promote the migration and invasion of tumor cells . Moreover, overexpressed HDAC6 has been found to be involved in multiple cancer-related signaling pathways, such as the activation of ERK1/2 phosphorylation .…”

“…15 Abnormally high expression of HDAC6 has been confirmed to promote the migration and invasion of tumor cells. 16 Moreover, overexpressed HDAC6 has been found to be involved in multiple cancer-related signaling pathways, such as the activation of ERK1/2 phosphorylation. 17 Consequently, the inhibition of HDAC6 has emerged as an efficacious therapeutic strategy for cancer, including HCC.…”