The Role of HDAC6 in Cancer

Abstract

Histone deacetylase 6 (HDAC6), a member of the HDAC family whose major substrate is α-tubulin, has become a target for drug development to treat cancer due to its major contribution in oncogenic cell transformation. Overexpression of HDAC6 correlates with tumorigenesis and improved survival; therefore, HDAC6 may be used as a marker for prognosis. Previous work demonstrated that in multiple myeloma cells, inhibition of HDAC6 results in apoptosis. Furthermore, HDAC6 is required for the activation of heat-shock factor 1 (HSF1), an activator of heat-shock protein encoding genes (HSPs) and CYLD, a cylindromatosis tumor suppressor gene. HDAC6 contributes to cancer metastasis since its upregulation increases cell motility in breast cancer MCF-7 cells and its interaction with cortactin regulates motility. HDAC6 also affects transcription and translation by regulating the heat-shock protein 90 (Hsp90) and stress granules (SGs), respectively. This review will discuss the role of HDAC6 in the pathogenesis and treatment of cancer.

Inhibition of HDAC6 Protein Enhances Bortezomib-induced Apoptosis in Head and Neck Squamous Cell Carcinoma (HNSCC) by Reducing Autophagy

“…Because HDAC6 plays a critical role in autophagy activation, we consistently found that knockdown of HDAC6 also enhanced Btz-induced apoptosis by inhibition of autophagy and UPR. Involvement of HDAC6 in aggresome formation and UPRmediated autophagy is well established in many neurodegenerative disease studies and has recently been implicated in chemoresistance (26). Concomitantly, our data also show a critical role for HDAC6 in aggresome formation upon accumulation of unfolded/misfolded proteins followed by the Btz treatment in HNSCC cells.…”

“…HDAC6 Is Required for Aggresome Formation and Induction of Autophagy in HNSCC Cells-Recently, it has been shown that HDAC6 was involved in gathering scattered polyubiquitylated CPAs and transporting them to the microtubule organizing center to promote aggresome formation (26,27). To determine whether HDAC6 played a role in Btz-induced aggresome formation and autophagy induction in SCC cells, we stably knocked down HDAC6 using shRNA (HDAC6KD) in SCC1 cells (Fig.…”

“…However, how TSA re-sensitizes the HNSCC cells, and the cross-talk between UPR, autophagy, and apoptosis to develop chemoresistance remains an important issue that needs to be addressed. Several studies have highlighted the role of HDAC6, an HDAC class IIB cytoplasmic tubulin deacetylase, in the clearance of CPAs through the formation of a single juxtanuclear inclusion body called the aggresome (26,27). The subsequent autophagic degradation of the aggresome to diminish the population of CPAs in the cytoplasm to alleviate ER stress upon proteasome inhibition and ER stress has been well established in multiple myeloma cells and isolated mouse embryo fibroblasts (28,29).…”

Development of an ELISA-Based HDAC Activity Assay for Characterization of Isoform-Selective Inhibitors

“…10 Among the class II proteins, HDAC6 is overexpressed in oral squamous cell carcinoma and breast cancer tumors. 11 Unlike other HDAC isoforms, HDAC6 plays important roles in multiple cancer-relevant biological processes that are not epigenetic in nature.…”

Cellular defence or viral assist: the dilemma of HDAC6

“…HDAC6, in particular, has distinct structure features and unique cytoplasmic functions in the regulation of cytoskeleton, cell migration, cell reprogramming and pluripotency [4,5]. Upregulation or activation of HDAC6 has also been implicated in tumorigenesis, neurodegenerative diseases and inflammatory disorders [6,7], implying HDAC6 is a potential therapeutic target for pharmacological intervention strategy. While the list of cytoplasmic acetylated proteins controlled by HDAC6 is rapidly growing, the function of HDAC6 in viral infection is still poorly understood.…”