Histone Deacetylase Inhibitors: A New Treatment Option in Cancer
Even though cancer is considered 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 two enzymes control it: histone acetyltransferases (HATs) and histone deacetylases (HDACs).
HAT transfers the acetyl group from acetyl co-enzyme A to lysine residues on the histones that make up the core. This is thought to loosen DNA, giving transcription factors and RNA polymerase greater access to it. HDAC, on the other hand, removes the acetyl groups, which compacts chromatin and narrows access to DNA. Aberrant acetylation of the histone tail by these enzymes is associated with carcinogenesis, and altered activity of these enzymes can change the expression patterns of various genes.
Histone Deacetylases (HDACs)
HDACs cause transcriptional repression of genes by deacetylating lysine residues on histone tails. HDACs also deacetylate non-histone proteins, 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 that regulate various cellular processes. However, over-expression and abnormal recruitment of HDACs to the promoter region of various tumor suppressor genes may trigger tumor initiation and progression. A number of studies have reported high levels of HDAC expression in various tumors compared to normal cells. Researchers reported increased expression of HDAC1 in gastric, prostate, colon, and breast carcinomas. They found elevated expression of HDAC2 in colon cancer, and high levels of HDAC6 expression in breast cancer.
Beyond over-expression, aberrant recruitment of these enzymes to specific promoter regions may also promote tumor invasion and metastasis. For example, E-cadherin is a transmembrane protein found in epithelial cells that plays an important role in cell adhesion. Invasive carcinomas show reduced expression or loss of function of E-cadherin. When the transcription factor Snail recruits HDAC1 and HDAC2 to the promoter region of E-cadherin, it reduces E-cadherin expression.
Beyond histone deacetylation, HDACs also deacetylate non-histone proteins. For example, mammalian HDAC1, 2, and 3 impair the function of the tumor suppressor gene p53. HDACs also alter the transcriptional activity of the transcription factor E2F, c-Myc, nuclear factor kB, and HIF-1 α. HDAC6 regulates the chaperone activity of the heat shock protein Hsp90. Most of Hsp90’s client proteins are protein 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)
As researchers have learned more about the roles HDACs play in cancer, they’ve worked to identify potent inhibitors. The HDIs identified so far induce growth arrest, differentiation, and apoptosis in tumor cells. These inhibitors induce the cell cycle regulatory protein p21 and the apoptotic proteins Bax and PUMA. HDIs can also down-regulate various survival signaling pathways and disrupt the cellular redox state. Because of this, HDIs have drawn growing interest as anti-cancer agents in recent years.
Several HDIs are currently in clinical trials, both as monotherapy and in combination 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, multiple myeloma, and lung, breast, pancreas, renal, and bladder cancers, as well as melanoma and glioblastoma. So far, most responses to HDIs as single agents have occurred in advanced hematologic tumors, with fewer responses in solid tumors.
In 2006, the Food and Drug Administration (FDA) approved the HDI vorinostat (suberoylanilide hydroxamic acid, SAHA) to treat relapsed and refractory cutaneous T-cell lymphoma (CTCL). In November 2009, the FDA also approved another HDI, romidepsin (depsipeptide), for CTCL, and in 2011 for peripheral T-cell lymphoma patients who had already received prior therapy.
Even though HDIs have shown anti-tumor activity across a broad variety of hematologic and solid tumors in clinical trials, only a portion of patients with a given diagnosis showed a therapeutic response. A detailed understanding of HDIs’ mechanisms of action, as well as their mechanisms of resistance, would help researchers identify markers and formulate strategies to enhance HDIs’ efficacy in the clinic.
Further reading:
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.
