Epigenetic remodelling drugs in cancer treatment

By Sabino Méndez Pastor

There is no doubt that cancer is one of the major health burdens of our time. The World Health Organisation (World Health Organisation, 2021) estimates that it claimed 9.6 million lives in 2018, making it the second leading cause of death globally. Cancer chemotherapy has been one of the most important medical advances in the last few decades. Currently, it represents the most promising option for cancer treatment. However, the efficacy of chemotherapy is still limited by drug resistance, serious side-effects and narrow therapeutic indexes (Eckschlager et al., 2017; Mansoori et al., 2017). The emergence in recent years of targeted therapies directed against cancer specific pathways and targets could help overcome the problems associated with chemotherapy. One of these targeted cancer therapies is represented by epigenetic remodelling drugs. 

Epigenetic factors are defined as inheritable modifications of chromatin that influence gene expression without involving changes in the DNA sequence. These include histone modifications, DNA methylation, non-coding RNAs and chromatin organisation states. Cancer is not only caused by genetic alterations but also involves epigenetic aberrations that can contribute to anticancer drug resistance. For instance, the reprogramming of cancer cells into pluripotent stem cells via epigenetic remodelling is one of the main reasons of cancer relapse and drug resistance. During chemotherapy, cancer stem cells can enter a dormancy phase and escape elimination. These residual cancer stem cells can be triggered to start proliferating again, resulting in recurrent and chemoresistant disease (Patnaik and Anupriya, 2019). Epigenetic processes have therefore emerged as novel therapeutic targets as they are directly associated with cancer pathogenesis and their inherent plastic nature represents a window of opportunity for specific inhibitors of proteins involved in epigenetic modifications. 

DNA is wrapped around histone proteins which interact with their histone tails to facilitate DNA packaging in the nucleus. Modification of histones by acetylation plays a key role in the epigenetic regulation of gene expression. Histone tail acetylation results in less condensed chromatin structure, making genes more accessible to transcription factors and thus upregulating gene expression. Histone acetyltransferases (HATs) and deacetylases (HDACs) regulate histone acetylation states. HATs catalyse the transfer of an acetyl group from acetyl-CoA to lysine residues of histone tails while HDACs remove it (Eckschlager et al., 2017). Overexpression of HDACs in cancer has been shown to promote migration, invasion, tumorigenesis and metastasis as HDAC regulates several proteins that play major roles in cancer progression such as STAT3, tumour protein p53, β-catenin, Foxp3 and NF-Kβ (Hull, Montgomery and Leyva, 2016). Upregulation of HDAC1 has been observed in prostate, gastric, lung, oesophageal, breast and colon cancer whereas HDAC2 was found to be upregulated in cervical, gastric and colorectal cancer (Patnaik and Anupriya, 2019). HDAC inhibitors (HDACi) have emerged as novel drugs with potent anticancer activity in both preclinical and clinical trials. They induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and stimulate immune responses against tumours (Eckschlager et al., 2017). In addition, HDACi decrease metastasis by reducing the expression of genes involved in migration and epithelial-to-mesenchymal transition (Patnaik and Anupriya, 2019). HDACis vorinostat (SAHA), romodespin and belinostat have already been approved by the Food and Drug Administration (FDA) for treatment of some T cell lymphomas and Panobinostat for multiple myelanoma (Eckschlager et al., 2017).

Another important epigenetic factor is DNA methylation. It is defined as the covalent addition of a methyl group to a cytosine residue followed by a guanine, known as a CpG dinucleotide. High methylation levels in the promoter region of a gene prevent transcription machinery from binding and reduce the expression of that gene. In cancer, aberrant DNA methylation patterns result in the silencing of several key tumour suppressor genes, leading to tumour growth. Inactivation by DNA methylation of genes involved in tumour suppression, DNA repair, cell-cycle regulatory machinery, apoptosis, angiogenesis and metastasis has been demonstrated in a wide range of tumour types (Patnaik and Anupriya, 2019). DNA methyltransferases (DNMTs) are responsible for the inheritance of methylation marks. During DNA replication, DNMT1 recognises CpG dinucleotides methylated on the original strand but not in the newly synthesised strand and methylates the unmethylated cytosines. Overexpression of DNMT1 has been observed in almost all cancer types, maintaining high methylation levels (Heerboth et al., 2014). DNMT inhibitors (DNMTi) thus represent a promising option to treat cancer. DNMTi decitabine and azacytidine are approved for the treatment of myelodysplastic syndrome and acute myeloid leukaemia, and they are being tested as adjuvant therapies for colon, ovarian and lung cancer (Giri and Aittokallio, 2019). Besides this, methylation of specific genes can be considered as potential biomarkers for the early detection of cancers. For instance, several tumour suppressor genes such as CMTM3, SSTR2 and MDFI are remarkably hypermethylated in the early stage of colorectal cancer when compared with adjacent normal colorectal tissues (Li et al., 2017). 

Histone tails can also be methylated. Contrarily to acetylation, histone methylation results in condensed chromatin states and transcriptional silencing. Changes in histone methylation patterns have been associated with many types of cancer. Histone 3 lysine 4 dimethylation (H3K4me2) is down-regulated in lung, kidney, prostate, breast and pancreatic cancer and H3K27me3 is downregulated in gastric carcinoma. Histone methyltransferases (HMTs) catalyse the methylation of histone tails and are upregulated in several cancer types (Patnaik and Anupriya, 2019). For instance, Enhancer of zeste homolog 2 (EZH2) has been associated with repression of tumour suppressor and epithelial-to-mesenchymal transition (EMT) related genes. EZH2 is overexpressed in many solid tumours including breast, ovarian, prostate, melanoma and glioblastoma as well as lymphomas where it correlates with disease progression and poor prognosis. EZH2 inhibitor tazemostat has received approval for advanced epithelioid sarcoma and has shown positive results in preclinical trials for colorectal cancer treatment. Many other HMT inhibitors (HMTi) are currently in development, some of which are being tested in clinical studies (Rugo et al., 2020).

In conclusion, epigenetic remodelling drugs such as HDACi, DNMTi and HMTi are promising targeted therapies for cancer. Vorinostat, Panobinostat, decitabine and tazemostat are some examples of this kind of agents that are already in use and more are in their way for approval. However, further refinement of epigenetic remodelling drugs is needed to overcome some important limitations. The reversible nature of epigenetic changes makes remethylation a major problem that needs to be resolved. Epigenetic drugs are rapidly degraded in the body although improved drug delivery systems are being investigated to enhance drug stability, permeability and retention. Finally, many epigenetic drugs like azacytidine and decitabine are highly toxic in nature. Plant based drugs are drawing attention as by being naturally derived, they have shown to produce less or non-toxic effects on normal cells (Patnaik and Anupriya, 2019). Still, combined therapies of standard chemotherapy with epigenetic targeting drugs could help to overcome drug resistance as it can induce the reactivation of genes required for the effect of chemotherapeutic drugs.


Eckschlager, T. et al. (2017) ‘Histone deacetylase inhibitors as anticancer drugs’, International Journal of Molecular Sciences. MDPI AG. doi: 10.3390/ijms18071414.

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Patnaik, S. and Anupriya (2019) ‘Drugs targeting epigenetic modifications and plausible therapeutic strategies against colorectal cancer’, Frontiers in Pharmacology. Frontiers Media S.A. doi: 10.3389/fphar.2019.00588.

Rugo, H. S. et al. (2020) ‘The Promise for Histone Methyltransferase Inhibitors for Epigenetic Therapy in Clinical Oncology: A Narrative Review’, Advances in Therapy. Adis, pp. 3059–3082. doi: 10.1007/s12325-020-01379-x.

World Health Organisation (2021). Cancer. Available at: https://www.who.int/health-topics/cancer#tab=tab_1 (Accessed: 21 June 2021).

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