Inhibition of histone deacetylases in cancer therapy: lessons from leukaemia

Abstract

Histone deacetylases (HDACs) are a key component of the epigenetic machinery regulating gene expression, and behave as oncogenes in several cancer types, spurring the development of HDAC inhibitors (HDACi) as anticancer drugs. This review discusses new results regarding the role of HDACs in cancer and the effect of HDACi on tumour cells, focusing on haematological malignancies, particularly acute myeloid leukaemia. Histone deacetylases may have opposite roles at different stages of tumour progression and in different tumour cell sub-populations (cancer stem cells), highlighting the importance of investigating these aspects for further improving the clinical use of HDACi in treating cancer.

Figure 1

HDACs class I, II, IV mutations in human cancer. (A) Histone deacetylases class I, II and IV mutations across different human cancers. The histogram shows an overview of the frequency of mutations (missense) of each HDAC (classes I, II and IV) across different human cancers (analysis was performed on data downloaded from cBioPortal, see Supplementary Table S1 for a guide to the abbreviations, and the description for each cancer subtype of sample size). (B) Distribution of mutations across HDAC9 and HDAC4 coding sequences. Lolliplot graph of missense mutations found across all human cancers for HDAC9 (upper panel) and HDAC4 (lower panel). Note that though mutations are equally distributed along the entire coding sequence, in both cases the most frequent mutation is localised within the histone deacetylase catalytic domain. For HDAC4, in 13 patients the same mutation introduces a frameshift in the middle of the deacetylase domain, leading most likely to a functional inactivation of the domain. The two graphs were obtained by using the cBioPortal tool ‘MutationMapper' (Cerami et al, 2012).

Figure 2

A time-dependent role for HDACs in leukaemia development. (A) During the preleukaemic phase of APL, HDAC1/2 act as tumour suppressors, and their knockdown results in accelerated leukaemia development. This can be because of higher frequency of additional hits, or to direct transformation of PML-RAR preleukaemic cells. (B) During the leukaemic phase, knockdown of HDAC1/2 cause differentiation and then apoptosis of APL cells, with an extended lifespan of the leukaemic mice.

Figure 3

Histone deacetylase inhibitors have distinct effects on tumour cell sub-populations. (Upper panel) Histone deacetylase inhibition by VPA treatment of APL mice results in differentiation of bulk leukaemic cells and prolonged survival, but as LICs are not targeted disease recurs. (Middle panel) Treatment with arsenic leads to tumour regression because of significant reduction in the number of LICs, and progressive tumour exhaustion, but tumour growth in the short term may continue because of bulk of leukaemic cells and – in high-risk aggressive disease forms – lead to patient death. (Bottom panel) Combining the two treatments, by acting on both tumour cell sub-populations, may offer the best perspective in terms of disease control and LIC eradication.