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What Can Histone Methylation Patterns in Kidney Cancer Teach Us About Disease Progression & New Treatments Options?

Kidney cancer epigenetics

June 19, 2019

Kidney cancer is one of the 10 most common cancers in both men and women in the United States, and renal cell carcinoma (RCC) is the most common and deadly form of kidney cancer.

The main treatment for most patients with kidney cancer involves surgery to try to remove all or some of the affected kidney to remove tumors while still preserving kidney function. These treatments are often not effective, highlighting the need for additional and better therapeutic options.

What is Renal Cell Carcinoma?

Renal cell carcinoma is an especially difficult type of kidney cancer to treat because it is often malignant and resistant to traditional chemotherapy and radiotherapy treatments. RCC makes up approximately 90% of the cases of kidney cancer worldwide, which leads to about 120,000 deaths each year. Renal cell carcinoma is a serious disease and doctors clearly need better ways to treat it.

Epigenetics of Renal Cell Carcinoma

Tumors associated with many different cancer types have epigenetic changes that can be used as diagnostic or prognostic biomarkers and mutations in epigenetic enzymes can directly contribute to oncogenesis and metastasis for some cancers.

However, specific epigenetic profiles associated with renal cell carcinomas have not yet been well established.

A team of researchers in India recently published a paper in the journal Science Reports that described the results from a study that investigated the patterns of histone H3 methylation on lysine 4 (H3K4) to learn more about the epigenetic changes that correlated with renal cell carcinoma progression and metastasis.

The researchers found that decreased levels of all forms of methylated H3K4 (monomethylated/H3K4me1, dimethylated/H3K4me2, and trimethylated/H3K4me3) were associated with both advanced stages of cancer progression and metastasis. Therefore, H3K4 methylation is a prognostic biomarker for RCC.

What Controls H3K4 Methylation Levels in Renal Cell Carcinoma?

The scientists next investigated the mechanism responsible for regulating the observed changes in H3K4 methylation with experiments that measured the expression levels of several different histone methyltransferase (HMT) and histone demethylase (HDM) enzymes.

Expression levels of several HMT enzymes were altered in RCC tumors relative to normal tissue, but the extent of the changes was not statistically significant. These results suggest that the changes in histone methylation levels were not caused by changes in the levels of histone methyltransferase enzymes.

The changes in levels of HDM enzymes, on the other hand, were significantly increased in the RCC tumor samples, suggesting that elevated histone demethylase activity contributed to the decreases seen in the global levels of histone H3K4 methylation.

Follow-up studies utilizing siRNA-mediated knockdowns were performed on two HDMs, LSD2 and KDM5A. Knocking down either HDM enzyme in RCC cell lines resulted in decreased cell viability and increased levels of apoptosis, with the effect being more significant in the LSD2 knockdown cells. These observations are consistent with the idea that LSD2 and KDM5A contribute to the development and progression of renal cell carcinoma.

Can Epigenetic Drugs Improve Treatment of Kidney Cancer?

Since levels of two histone demethylase enzymes are significantly upregulated in renal cell carcinoma the authors of the study suggested that these enzymes, LSD2 and KDM5A, are good potential therapeutic targets to treat RCC.

These enzymes are druggable with small molecules and other compounds, and several major pharmaceutical companies have drug development pipelines that focus on inhibiting HDMs. Therefore, it seems likely that epigenetic inhibitors, such as drugs that target LSD2 and KDM5A, will likely become a standard therapeutic strategy for different cancers in the future.

More research on renal cell carcinoma aimed to advance and innovate treatments will hopefully continue to progress rapidly to give physicians more ways to treat the many people that develop RCC and other types of kidney cancer.

Reference: Kumar, A. et al. Reduction in H3K4me patterns due to aberrant expression of methyltransferases and demethylases in renal cell carcinoma: prognostic and therapeutic implications. Sci. Rep. 9: 8189. (2019)

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