Even though cancer is considered as a disease of genetic defects, various studies have shown that epigenetic changes also play an important role in the onset and progression of cancer. Histone acetylation is one of the important epigenetic modifications, and is controlled by two enzymes: histone acetyltransferases (HATs) and histone deacetylases (HDACs). HAT transfers the acetyl group from the acetyl co-enzyme A to lysine residues of the histones comprising the core. This is thought to loosen DNA resulting in greater access to DNA for transcription factors and RNA polymerase. HDAC on the other hand, removes the acetyl groups, resulting in the compaction of chromatin thus narrowing access to DNA. Aberrant acetylation of the histone tail by these enzymes is associated with carcinogenesis. Expression patterns of various genes may become changed due to the altered activities of these enzymes.
Histone Deacetylases (HDACs)
HDACs cause transcriptional repression of genes by deacetylating lysine residues on histone tails. HDACs also cause deacetylation of non-histone proteins thus altering the transcriptional activity of p53 (tumor suppressor gene), E2F (transcription factor), c-Myc (transcription factor), nuclear factor kB (NF-kB), hypoxia inducible factor 1α (HIF-1 α), estrogen receptor α, and androgen receptor complexes.
HDACs in Cancer
HDACs are important enzymes in regulating various cellular processes. However, over-expression and abnormal recruitment of HDACs to the promoter region of various tumor suppressor genes may cause tumor initiation and progression. A number of studies have reported a high level of expression of HDACs in various tumors compared to normal cells. Increased expression of HDAC1 was reported in gastric, prostate, colon, and breast carcinomas. Elevated expression of HDAC2 was found in colon cancer. High levels of expression of HDAC6 were reported in breast cancer. In addition to the over-expression, aberrant recruitment of this enzyme to specific promoter regions may also promote tumor invasion and metastasis. For example, E-cadherin is a transmembrane protein that is found in epithelial cells and plays an important role in cell adhesion. Invasive carcinomas exhibit reduced expression or loss of function of E-cadherin. Recruitment of HDAC1 and HDAC2 to the promoter region of E-cadherin by transcription factor Snail caused reduced expression of E-cadherin.
In addition to histone deacetylation, HDACs also deacetylate non-histone proteins. For example, mammalian HDAC1, 2, and 3 impair the function of tumor suppressor gene p53. HDACs also alter the transcriptional activity of transcription factor E2F, c-Myc, nuclear factor kB, and HIF-1 α. The chaperone activity of the heat shock protein Hsp90 is regulated by HDAC6. Most of the client proteins of Hsp90 are proteins kinases (c-Raf, MEK, Akt, HER-2) or transcription factors (androgen receptor, progesterone receptor, estrogen receptor) associated with cell proliferation, survival, and signaling.
Histone Deacetylase Inhibitors (HDIs)
With the increasing knowledge of the roles of the HDACs in cancer, efforts have been made to identify potent inhibitors. HDIs identified so far have been shown to induce growth arrest, differentiation, and apoptosis in tumor cells. These inhibitors were found to induce cell cycle regulatory protein p21, apoptotic proteins Bax, and PUMA. HDIs were also able to down-regulate various survival signaling pathways and were able to disrupt the cellular redox state. Therefore, in recent years HDIs have drawn interest as anti-cancer agents. Several HDIs are currently in clinical trials both in monotherapy and in combination therapy with other anti-tumor drugs. A review by Tan et al. (2010) reported that at least 80 clinical trials are underway, testing more than 11 different HDIs in hematologic and solid tumors, including leukemias, lymphomas, and multiple myeloma, lung, breast, pancreas, renal, and bladder cancers, melanoma, glioblastoma. To date, most of the responses using HDIs as single agents were observed in advanced hematologic tumors and few were observed in solid tumors. In 2006, HDI vorinostat (suberoylanilide hydroxamic acid, SAHA) was approved by the Food and Drug Administration (FDA, USA) for the treatment of relapsed and refractory cutaneous T-cell lymphoma CTCL. In November, 2009, the FDA also approved another HDI romidepsin (depsipeptide) for the treatment of CTCL, and in 2011 for the treatment of peripheral T-cell lymphoma patients who have already received prior therapy.
Even though HDIs have shown anti-tumor activity across a broad variety of hematologic and solid tumors in the clinical trials, only a portion of patients with a given diagnosis showed therapeutic response. Therefore, a detailed understanding of the mechanisms of action, as well as mechanisms of resistance, of HDIs would help to identify markers and formulate strategies which may enhance the efficacy of HDIs in the clinic.
1. Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov. 2002;1(4):287-299.
2. Lane AA, Chabner BA. Histone deacetylase inhibitors in cancer therapy. J Clin Oncol. 2009;27(32):5459-5468.
3. Ropero S, Esteller M. The role of histone deacetylases (HDACs) in human cancer. Mol Oncol. 2007;1(1):19-25.
4. Shankar S, Srivastava RK. Histone deacetylase inhibitors: mechanisms and clinical significance in cancer: HDAC inhibitor-induced apoptosis. Adv Exp Med Biol. 2008;615:261-298.
5. Tan J, Cang S, Ma Y, Petrillo RL, Liu D. Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J Hematol Oncol. 2010;3:5.