Discussion and Perspective

Though many lines of evidence implicate HDACs in the regulation of tumori-genesis by deacetylation of nonhistones, there remains little direct evidence linking HDACs to cancer. Whether HDACs are primarily tumor promoters or tumor suppressors is difficult to discern. For example, SIRT1 deacetylates and deactivates some tumor suppressors, such as p53 and Rb, and thus represses apoptosis, suggesting that SIRT1 acts as a tumor promoter. The fact that SIRT1 is over-expressed in a variety of tumor tissues further argues for a role of SIRT1 as a tumor promoter (Hida et al. 2007; Huffman et al. 2007). However, several lines of evidence suggest SIRT1 is a tumor suppressor. Some of the more convincing evidences are as follows. First, SIRT1 inhibits the functions of tumor-promoting proteins such as survivin and beta-catenin (Firestein et al. 2008; Wang et al. 2008). Second, mice overexpressing SIRT1 show no tumor formation compared to the control (Banks et al. 2008; Pfluger et al. 2008). In fact, overexpression of Sirt1 in colon-cancer-prone APC~,+ mice reduced the levels of colon cancer (Firestein et al. 2008). Third, although there is no way to examine the roles of Sirt1 in carcinogenesis in homozygous knockout mice because of the embryonic lethality of Sirt1 analysis of the early embryos of Sirt1 mice revealed that Sirt1 deficiency results in genome instability and defects in DNA damage repair, suggesting that it has a tumor suppressor function (Wang et al. 2008). Fourth, resveratrol, a grape extract with chemo-preventive effects on some tumors such as leukemia and prostate cancer (Estrov et al. 2003; Hsieh and Wu 2000), was found to be an agonist of SIRT1 (Aziz et al. 2005; Howitz et al. 2003). Finally, SIRT1 could be up-regulated by some tumor suppressors, for example BRCA1. Up-regulation of SIRT1 by BRCA1 in turn inhibits the formation of BRCA1-mutation associated cancer (Wang et al. 2008).

It is not impossible to explain, or even reconcile, these apparent tumor-promoting and tumor-suppressing functions of SIRT1. For example, SIRT1's negative regulation on tumor suppressors, notably p53, might be cell context, temporality, and spatiality dependent. Laboratory cell culture is different from real tumor microenvironments, which are hypoxic and hotspots of inflammation, apoptosis, and angiogenesis. Therefore, the observation that SIRT1 deacetylates and deactivates some tumor suppressors may not reflect in vivo function. Whether SIRT1 (or the other HDACs) has a primary role of promoting tumor development, or inhibiting it, or some combination of effects, will remain a hot topic for many coming years.

Given that there are multiple steps and factors in the process of tumorigenesis, much more work awaits to clarify the role of HDACs in cancer. Initial identification of nonhistone proteins regulated by HDACs relied heavily on the use of antiacetyl lysine antibodies. However, this method is tedious and has many limitations related to the low affinity and low specificity of the currently available antiacetyl lysine antibodies. The lack of a conserved recognition motif for HDACs also contributes to the problem. Encouragingly, mass spectrometry has revealed that numerous nonhistone proteins undergo acetylation (Kim et al. 2006; Choudhary et al. 2009). As the technology for detection of protein acetylation/deacetylation becomes more advanced, we predict that even more acetylated proteins will be discovered, and reversible acetylation might be one of the most common PTM of proteins. Global acetylation analysis (may be termed "acetylationomics") under physiological or pathological conditions and studies that bridge "acetylationomics" and other "modificationomics" would help to fully elucidate the role of protein deacetylation and HDACs in diverse cellular processes.

Acknowledgments We thank Abuzar Kabir and the Moffitt Proteomics Core for technical help. The work in our lab is supported by grants to E.S. from the National Institutes of Health (NIH), and the Kaul Foundation. L.P. is a recipient of the American Heart Association Postdoctoral Fellowship.

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