The contribution of HDAC as a potential therapeutic agent for cancer

By Nishka Mahajan

DNA within cells carries an individual’s genetic information packaged in the form of chromatin – a dynamic structure comprising nucleosomes as fundamental building blocks. Each nucleosomal subunit is composed of a 147-base-pair DNA segment wrapped around an octamer of four core histone proteins (H2A, H2B, H3 and H4). Each of these core histone proteins possess a characteristic tail region that protrudes from the DNA-wrapped core. Histone tails are positively charged and densely populated with basic lysine and arginine residues, which can be extensively post-translationally modified (in response to intrinsic and external stimuli) to regulate chromatin. Epigenetic modifications (e.g., methylation, acetylation, and ubiquitination, amongst others) disrupt the condensed chromatin structure by altering the existing charge density between histones and DNA. This respectively impacts inter/intra nucleosomal interactions as genes are turned “on” and “off”. To maintain the stable structure of the chromatin, execute proper gene expression, and control the consequent biological outcome – a steady balance between specific modifications and modifiers is imperative.1, 2

Specifically, this article investigates the mechanism for histone acetylation. It is a reversible modification that takes place on the ε-amino group of lysine residues. This process is tightly controlled by a balance between two groups of enzymes carrying out opposing activities – histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs, as their name suggests, catalyse the acetylation of conserved lysine amino acids by transferring an acetyl group from a molecule of acetyl-coenzyme A to the ε-amino group on lysine. This addition neutralizes the positive charge on the lysine, disrupting the interaction between the tail and the negatively charged nucleosomal DNA. As a result, the condensed chromatin transforms into a more relaxed structure, making DNA more accessible to transcription factors. This promotes active transcription or gene activation. On the other hand, HDACs catalyse the removal of this acetyl group with a molecule of H2O (deacetylation). This yields a more compact chromatin structure that limits the accessibility of chromatin for transcription machinery, thereby playing a critical role in regulating transcription.2, 3 Aside from gene transcription, HATs and HDACs are not limited to histone proteins; they also target various non-histone proteins involved in different biological processes such as cell-cycle progression, differentiation, and apoptosis.4

Advances in genomic studies have implicated alterations/dysregulation in histone acetylation process to be associated with the uncontrolled cell growth seen in cancer. Eighteen HDAC enzymes are currently known to be present in humans. These can be subdivided into four major families. Class I (HDACs 1, 2, 3 and 8) are ubiquitously expressed in human cell lines and tissues in the nucleus; Class II (HDACs 4, 5, 6, 7, 9 and 10) exhibit tissue-specific expression and can shuttle between the nucleus and cytoplasm; Class III/sirtuins (SIRT1-7) depend on NAD+ and have a very distinct catalytic mechanism for deacetylation in relation to other classes of HDACs; lastly, Class IV has only one identified member, HDAC11, that is capable of deacetylating divergent histone sites, consequently making the substrate specificity low and functionally redundant in certain scenarios.2 Primarily Class I (HDACs 1, 2)and Class II HDACs are involved in regulating the proliferation of cancer cells. Overexpression of HDACs has been found in a variety of cancers, with a significant correlation in decreasing disease and overall survival along with predicting poor patient prognosis. Therefore, HDAC activity is a key mediator of survival and tumorigenic capacity, which makes it a compelling target for cancer therapy. Inhibitors targeting HADCs (HDACi) have been developed to modulate transcription and induce differentiation and cell-cycle arrest – targeting and killing dividing cancerous cells. HDACi directly binds to the HDAC-active site, blocking its access to the substrate and thereby causing an accumulation of acetylated histones. In 2006, Vorinostat (SAHA) was the first FDA-approved HDACi for the treatment of patients with refractory cutaneous T-cell lymphoma. Romidepsin (Istodax) was the second HDACi to gain approval in 2009. In addition, many other HDACi are currently under different stages of clinical assessment, with most being focused on haematological malignancies.4, 6

Over the past few years, interest in HDAC enzymes has rapidly increased. Since DNA methylation and histone modification are the main epigenetic hallmarks of a cancer cell, these have high potential to serve as anti-cancer therapeutic agents. Effects of HDAC inhibitors in animal model systems demonstrate that these agents preferentially affect tumour cells rather than causing general toxicity to the whole organism.7 Several ongoing clinical trials are examining the use of these agents in association with chemotherapeutic drugs, aiming at increasing their therapeutic efficiency (higher target specificity, more efficacious with less toxicity).8, 9 Among important issues to address are treatment resistance and the lack of comprehensive data regarding the quality-of-life changes associated with the use of HDAC inhibitors.10

References:

  1. Audia JE, Campbell RM. Histone Modifications and Cancer. Cold Spring Harbor Perspectives in Biology. 2016;8(4): a019521. https://doi.org/10.1101/cshperspect.a019521.
  2. Zhao Z, Shilatifard A. Epigenetic modifications of histones in cancer. Genome Biology. 2019;20: 245. https://doi.org/10.1186/s13059-019-1870-5.
  3. Li Y, Seto E. HDACs and HDAC Inhibitors in Cancer Development and Therapy. Cold Spring Harbor Perspectives in Medicine. 2016;6(10): a026831. https://doi.org/10.1101/cshperspect.a026831.
  4. Ropero S, Esteller M. The Role of Histone Deacetylases (HDACs) in Human Cancer. Molecular Oncology. 2007;1(1): 19–25. https://doi.org/10.1016/j.molonc.2007.01.001.
  5. Seligson DB, Horvath S, Shi T, Yu H, Tze S, Grunstein M, Kurdistani SK. Global histone modification patterns predict risk of prostate cancer recurrence. Nature. 2005;435(7046): 1262-1266. https://doi.org/10.1038/nature03672.
  6. Cheng Y, He C, Wang M, Ma X, Mo F, Yang S, Han J, Wei X. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduction and Targeted Therapy. 2019;4: 62. https://doi.org/10.1038/s41392-019-0095-0.
  7. Kramer OH, Gottlicher M, Heinzel T. Histone deacetylase as a therapeutic agent. Trends in Endocrinology & Metabolism. 2001;12(7): 294–300. https://doi.org/10.1016/S1043-2760(01)00438-6.
  8. Fang JY. Histone deacetylase inhibitors, anti-cancerous mechanism and therapy for gastrointestinal cancers. Journal of Gastroenterology and Hepatology. 2005;20(7): 988–994. https://doi.org/10.1111/j.1440-1746.2005.03807.x.
  9. Kouraklis G, Misiakos EP & Theocharis S. Histone deacetylase inhibitors as a potential therapeutic agent for human cancer treatment. Targeted Oncology. 2006;1: 34–41. https://doi.org/10.1007/s11523-005-0007-9.
  10. Bondarev AD, Attwood MM, Jonsson J, Chubarev VN, Tarasov VV, Schiöth HB. Recent developments of HDAC inhibitors: Emerging indications and novel molecules. British Journal of Clinical Pharmacology. 2021;87(12): 4577– 4597. https://doi.org/10.1111/bcp.14889.

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