A new study showed that it may be possible to cure type-1 diabetes (T1D) using two drugs that the FDA has already approved to treat sarcomas1-2. This study showed how insulin-producing cells could be regenerated in the pancreas. The drugs called GSK126 and Tazemetostat (Taz) treat cancer by silencing the gene that codes for a key enzyme, called Enhancer of zeste homolog 2 (EZH2) 3.

Diabetes affects about 400 million people worldwide and is responsible for 9.9% of deaths1. It is caused by the destruction of insulin-producing β-cells the islets of Langerhans, in the pancreas. This leads to an inability to properly regulate blood glucose and a dependence on insulin. Current treatments help control blood glucose levels, but they do not prevent, slow down, or reverse the decline in insulin-secreting β-cells. Still, it may be possible to transplant a whole new pancreas or islet. However, there is a shortage of available donors. Even when a donor is available, immunosuppressive medications are required. They can cause some very adverse side effects.

So, it is interesting that a whole new approach to treating T1D has emerged. The idea is to correct the defect that exists, not in the genome but in the epigenome. That is, our genome (all of our genes) is not a blueprint but a part of a larger dynamic system that allows the appropriate genes (DNA) to be transcribed into messenger RNA (mRNA) and then translated into proteins. For an organism to survive, it must be able to adapt to changes in its environment. To do this, the genes, mRNA, and proteins can be turned on or off by a layer of control that lies above the genome, as an addition to genetics. This layer is called the epigenome. Epigenetics is the study of how behavior and the environment cause changes that affect how genes work. One way that DNA transcription can be controlled is through positively charged histone proteins that wrap around the double-stranded DNA and neutralize about 50% of it. If the negatively charged DNA were not surrounded by histones, the DNA would not be able to be compacted into the small space provided by the cell nucleus, due to electrostatic repulsion. The arginine and lysine residues on histones provide convenient targets for one part of the epigenetic control of transcription. One way that they can be modified is by attaching a methyl group.

Histone lysine and arginine methylation is regulated dynamically at individual genes by recruiting enzymes called methyltransferases and demethylases. They catalyze the addition or removal of methyl groups. Lysine residues in histones can be methylated with one, two, or three methyls without affecting their charge. Arginine can be mono- or dimethylated. Methylation does not affect the ionic bonds between histones and DNA, but creates tags that can be identified by co-regulatory proteins. In differentiated cells, inactive portions of the genome are partitioned between different forms of repressive chromatin. Repressive structures with a compact structure are not accessible to enzymes that can catalyze the transcription of DNA into RNA. They can affect large regions of chromosomes. The tightly packaged mixture of DNA and histones form a structure called chromatin. The structure and function of chromatin is modulated by proteins that are associated with it. Improper control of chromatin structure can lead to T1D, cancer and many other diseases. One group of proteins that can do this combine to form a complex that is important in the development of plants and animals. Polycomb proteins 1 and 2 (PRC1 and PRC2) can form complex structures that repress transcription. It’s essential that the transcription of appropriate genes is turned off and on at appropriate times for an embryo to properly develop into a healthy baby and subsequently, an infant, child, and adult.

One part of PRC2 is the enhancer of the EZH2 catalytic subunit3. It is a histone methyltransferase. It catalyzes the methylation of histone number 3 at arginine number 27 (H3K27). This leads to transcriptional silencing of target genes. Additional polycomb group proteins attach to the H3K27 that form the repressive chromatin state. EZH2 overexpression occurs in many types of cancer and is correlated with tumorigenesis, metastasis, and a poor prognosis. The drug EPZ-6438 (tazemetostat) inhibits EZH2. It was approved by the FDA for the treatment of epithelioid sarcoma in 2020.

Fortunately, researchers have found that this same drug is able to inhibit EZH2 in β-cells that are in pancreatic islets. They synthesize, store and release insulin. In T1D, T-cells of the immune system selectively destroy the insulin-producing β-cells. This leads to a lifelong dependence on insulin for survival. The main function of EZH2 is to catalyze the methylation of H3 histone of H3K27Me3, which inhibits the transcription of target genes, such as tumor suppressor genes. EZH2 also forms complexes with transcription factors or directly binds to the promoters of target genes, leading to regulate gene transcriptions. It was already known that pancreatic ductal progenitor cells are a promising source for regenerating β-cells for T1D due to their inherent capacity for differentiation. Default transcriptional suppression tightly controls the regenerative potential. In the recent study, exocrine cells derived from juvenile and adult T1D donors that were treated with Tazemetostat had a phenotypic shift towards a β-like cell identity. Targeting EZH2 was needed for β-cell regenerative potential. Reprogrammed pancreatic ductal cells produced insulin and secretion in response to being given glucose1.

This is not the only promising development in treating diabetes. Tirzepatide, sold under the name Mounjaro, was approved for treating type-2 diabetes (T2D) in May 13; 2022. It is a synthetic combination of two peptides called GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide). They are called incretin hormones. They are secreted in the gut after consuming nutrients. They stimulate the production of insulin and a decrease in the concentration of blood glucose. So, work continues as researchers, physicians, and even pharmaceutical companies work together to develop treatments and cures for T1D, T2D, and many other diseases.

Notes

1 Al-Hasani, K. et al. EZH2 inhibitors promote β-like cell regeneration in young and adult type 1 diabetes donors. Signal Transduction and Targeted Therapy 9.1, Vol. 2, 2024.
2 Nield, D. Dysregulated lipid metabolism blunts the sensitivity of cancer cells to EZH2 inhibitor. Science Alert, 9 Jan., 2024.
3 Zhang, T. et al. Dysregulated lipid metabolism blunts the sensitivity of cancer cells to EZH2 inhibitor. EBioMedicine Vol. 77, 2022.