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.

Figure 1

HDAC6 functional domains. The only HDAC with two tandem catalytic domains, deacetylase domains (DD1 and DD2). Tubulin, Hsp90, and cortactin have been found to be HDAC6 substrates. The nuclear export signal (NES) prevents accumulation of the protein in the nucleus and the Ser-Glu-containing tetrapeptide (SE14) region ensures a stable anchorage of the enzyme in the cytoplasm. The linker between both DDs is able to bind dynein and the high affinity ubiquitin-binding zinc finger domain (ZnF-UBP).

Figure 2

CYLD-mediated inhibition of HDAC6 leads to a delay in the cell cycle. CYLD binds acetylated microtubules and inhibits HDAC6. Inhibition of HDAC6 leads to increased levels of acetylated ∝-tubulin and this induces more binding of CYLD to MTs. CYLD binds BCL-3, and in the presence of TPA blocks its nuclear translocation, thereby inhibiting cyclin-D1.

Figure 3

Cell stress response: activation of the aggresome pathway, HSPs, and transcriptional response. (a) Under nonstress conditions, protein degradation occurs through the proteasome. HDAC6 is sequestered by VCP/p97 and forms a basal complex with HSF1 and HSP90. This keeps HSF1 in its inactive form. (b) Inhibition of the proteasome leads to an increase of misfolded proteins. HDAC6 binds these ubiquitinated protein aggregates and the basal complex disassembles. This complex dissociation activates HSF1, which eventually activates HSPs. The protein aggregates are transported along the MTs to MTOC to form an aggresome and autophagic clearance is activated. HDAC6 can also modulate Hsp90 acetylation levels and affect the maturation of client proteins, such as the glucocorticoid and androgen receptors, impairing gene transcription activation.