To understand the role of individual HDACs in tumorigenesis it is of utmost importance to clarify the function of HDACs in proliferation, differentiation, and development by loss-of-function studies in animal models.
Since HDACs control many essential mechanisms during development and tissue maintenance, it is not surprising that deletion of individual HDACs leads to severe phenotypes in mice. Knockouts of HDAC1, 3, and 7 result in embryonic lethality due to impaired cell cycle (HDAC1 and 3) and endothelial dysfunction (HDAC7) (Bhaskara et al. 2008; Chang et al. 2006; Lagger et al. 2002; Montgomery et al. 2008). Mice lacking HDAC2, 4, and 8 exhibit peri/postnatal lethality due to cardiac abnormalities, ectopic cartilage ossification, and skull instability, respectively (Haberland et al. 2009b; Montgomery et al. 2007; Trivedi et al. 2007; Vega et al. 2004). In contrast, mice lacking HDAC5, 6, and 9 are viable and show only minor defects: deletion of HDAC5 and 9 leads to myocardial hypertrophy after stress, and HDAC6-deficient mice are the only HDAC mutant mice without an obvious phenotype (Chang et al. 2004; Zhang et al. 2002, 2008). Similarly to classical HDACs, loss of particular sirtuins results in developmental defects. Depending on the background, mice lacking SIRT1 exhibit embryonic lethality due to the reduced ability to repair DNA damage, die during the early postnatal period, or show sterility in adulthood (Cheng et al. 2003; McBurney et al. 2003; Wang et al. 2008). The absence of SIRT6 leads to numerous developmental defects and eventually death at about 4 weeks of age (Mostoslavsky et al. 2006), whereas SIRT7 deficiency results in cardiac failures and lifespan reduction (Vakhrusheva et al. 2008).
As discussed later, several members of the HDAC family have been shown to be either aberrantly expressed or mistargeted in different tumors and are consequently potential targets for cancer therapy. Fortunately, HDAC inhibitors are relatively well tolerated by patients and do not lead to as dramatic side effects as the phenotypes of HDAC knockout mice would suggest. The contrasting phenotypes between genetic deletion and pharmacological inhibition might be explained by the following facts: (1) While genetic deletion is permanent, HDAC inhibitors act transiently. (2) Ablation of HDACs leads to their outright inactivity, whereas their pharmacological inhibition might be incomplete. (3) As components of multisubunit complexes, certain deacetylases might have also nonenzymatic functions such as stabilization of corepressor complexes. Genetic deletion of HDACs results in their complete absence annihilating both the catalytic activity and their potential scaffolding function. In contrast, most HDAC inhibitors do not affect the assembly and integrity of HDAC-containing multisubunit complexes [reviewed in Haberland et al. (2009c)]. (4) Loss of HDACs can cause different effects in the developing and the adult organism. For instance, combined ablation of HDAC1 and HDAC2 is lethal in early development, whereas deletion in adult, postmitotic cells is well tolerated (Haberland et al. 2009a; Yamaguchi et al. 2010). This is in line with the particular HDAC inhibitor sensitivity of fast cycling cells such as tumor cells.
There are several mechanisms leading to a deregulated HDAC activity observed in many cancer types. HDACs can be mutated, changed in their expression levels, or aberrantly recruited in tumor cells.
The involvement of HDACs in cancer development has been initially demonstrated for hematological malignancies, where aberrant recruitment of HDAC-containing complexes to specific promoters by fusion proteins resulting from chromosomal translocations leads to abnormalities in differentiation and proliferation of myeloid cells (Mercurio et al. 2010; Ropero and Esteller 2007) (see Sects. 2.2 and 3.1). Structural mutations affecting HDAC expression and/or activity appear to be rare in tumors. To date, the only mutation identified in an HDAC gene is a frameshift in the HDAC2 gene, leading to the loss of HDAC2 protein and activity in human endometrial and colon cell lines (Ropero et al. 2006).
Strikingly, numerous clinical studies in cancer patients have established that the most prevalent alteration of HDAC function in tumors is overexpression. Increased mRNA as well as protein levels for different HDAC family members have been reported for a wide variety of human malignancies (listed in Sects. 3.1-3.7). Although a huge body of evidence indicates a crucial role of deregulated HDAC expression in cancer development, the mechanisms underlying HDAC overexpression in tumors are still poorly understood.
Only recently, deregulated miRNA expression has been attributed to aberrant HDAC expression in tumors. Noonan et al. have identified a miRNA targeting HDAC1 (miR-449), which induces cell cycle arrest and apoptosis of prostate cancer cells (Noonan et al. 2009). Interestingly, miR-449 is frequently downregulated in prostate cancer. A similar mechanism of regulation has been described for HDAC4
in hepatocellular carcinoma (Zhang et al. 2010), where decreased levels of miR-22, which targets HDAC4, have been correlated with worse prognosis.
In contrast to permanent and irreversible cancer-associated genetic abnormalities such as overexpression of oncogenes or mutation of tumor suppressor genes, the elevated levels of HDAC activity can be in principle modulated due to the dynamic nature of histone modifications. Therefore, inhibiting HDAC activity appears to be an attractive approach in cancer therapy. However, due to the delicate balance of histone acetylation - which controls expression of many genes involved in crucial cellular processes - and the fact that HDACs can affect the function of many nonhistone targets, it is difficult to predict the benefits, risks, and potential side effects of HDAC inhibition.
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