Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors

Abstract

Histone deacetylase inhibitors (HDIs) are a new class of drugs with significant antileukemic activity. To explore mechanisms of disease-specific HDI activity in acute myeloid leukaemia (AML), we have characterised expression of all 18 members of the histone deacetylase family in primary AML blasts and in four control cell types, namely CD34 þ progenitors from umbilical cord, either quiescent or cycling (post-culture), cycling CD34 þ progenitors from GCSF-stimulated adult donors and peripheral blood mononuclear cells. Only SIRT1 was consistently overexpressed (42 fold) in AML samples compared with all controls, while HDAC6 was overexpressed relative to adult, but not neo-natal cells. HDAC5 and SIRT4 were consistently underexpressed. AML blasts and cell lines, exposed to HDIs in culture, showed both histone hyperacetylation and, unexpectedly, specific hypermethylation of H3 lysine 4. Such treatment also modulated the pattern of HDAC expression, with strong induction of HDAC11 in all myeloid cells tested and with all inhibitors (valproate, butyrate, TSA, SAHA), and lesser, more selective, induction of HDAC9 and SIRT4. The distinct pattern of HDAC expression in AML and its response to HDIs is of relevance to the development of HDI-based therapeutic strategies and may contribute to observed patterns of clinical response and development of drug resistance.

HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination

“…Another report identified positive HDAC6 staining with decreased survival in ER-positive breast cancer patients, using HDAC6 as a prototypical estrogen-regulated gene (Yoshida et al, 2004). HDAC6 levels were also found elevated in primary acute myeloid leukemia blasts compared to normal adult cells (Bradbury et al, 2005).…”

Epigenetics provides a new generation of oncogenes and tumour-suppressor genes

“…We can view the picture from this angle and hypothesise that there is increased recruitment of SIRT1 to the K16-H4 position in repeat DNA sequences in the transformed cell. In this regard, overexpression of SIRT1 is observed in leukemia cells (Bradbury et al, 2005). For HDACs with a broader deacetylation specificity than SIRT1, such as HDAC1 and HDAC2, no somatic mutations in tumours have been described, but a dysregulated expression seems to be a common feature of human neoplasia (Gibbons, 2005).…”

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

“…SIRT1 is overexpressed in multiple primary solid tumors and hematopoietic malignancies (Bradbury et al, 2005;Huffman et al, 2007;Jang et al, 2008Jang et al, , 2009Jung-Hynes et al, 2009;Nosho et al, 2009). Inhibition of SIRT1 suppresses growth and promotes apoptosis in human cancer cells (Luo et al, 2001;Vaziri et al, 2001;Chu et al, 2005;Ford et al, 2005;Ota et al, 2006;Kojima et al, 2008;Jung-Hynes et al, 2009), but has little impact on the survival of normal cells (Ford et al, 2005;Jung-Hynes et al, 2009).…”