Prostate cancers remain localized in the majority of cases, giving affected individuals a good chance of survival. However, about 20% of patients develop incurable metastatic prostate cancer. Medical research has not yet adequately explained why metastases occur in some people and not in others. Scientists deem that genetic variability and speicif epigenome changes may lay beneath this phenomenon. Epigenomic changes refer to enzymatic modifications added to chromatin in order to switch-on or turn-off gene expression. This process is very delicate since any slight variation may trigger cellular anomalies leading to cancer development. Protein methylation and acetylation are among the most represented ways inside the cell nucleus to modify gene transcription upon any external stimulus. Histone and HMG proteins are usually tightened to DNA giving the proper folding and stability to chromatin.
They regularly undergo processes of acetylation/deacetylation operated by the HAT/HDAC axis, while protein methylation/demethylation is regulated by histone methyltransferases and demethylases (HMTs/MDMs). HMT classes of enzymes have been found to be either mutated or changed in expression within cancer cells. Carcinomas of lung, breast, colon and some sarcomas are examples where HMT mutations can be found. Prostate cancer is another type of tumor sometimes harboring a change of expression in epigenetic proteins. A research team at MedUni Vienna has now discovered specific changes in one of therse protein that drive the growth and spread of prostate cancer. In the study, the researchers investigated the role of the histone methyltransferase KMT2C in prostate cancer. Previous studies have shown evidence of tumour suppressive roles for KMT2C and it has been proposed its involvement in cellular growth, stemness and epithelial differentiation.
Prostate cancer may harbor up to 7% cases where the KMT2C gene is mutated. It is known that if KMT2C loses this regulatory ability due to typical cancer-related mutations, this enhances the activity of the cancer gene MYC. This in turn causes malignant cells to divide at an increased rate, driving both growth and spread of the cancer, by suppressing the INK4 gene involved in cellular replication. KMT2C mutation status can be measured via a blood test, allowing early diagnosis of potentially aggressive progression in prostate cancers. Therefore, the knowledge gained about the effects of KMT2C mutations may also generate new momentum for the diagnosis and treatment of prostate cancer. HMT inhibitors are already available and some of them are already sperimentally employed to treat some forms of cancer. Most of therm, however, do not distinguish among the tens of HMTs isoforms.
In their stead, MYC inhibitors could be used to prevent increased cell division, and hence metastasis, and it is hoped that further scientific studies will substantiate this finding. Besides its role in cellular proliferation, c-Myc protein has been recognized as regulating epithelial-to-mesenchymal (EMT) transition in malignancy. This process makes cancer cells even more immature (embryonic-like) and in allows them to acquire a metastatic potential. MYC inhibitors are relatively new anticancer drugs that have already been tested in clinical trials. Since resistant prostate cancer harbors androgen receptor mutations that unhinges the connection between male hormones and their receptors, MYC inhibitors could therefore bypass this inconvenient to be used in metastatic prostate cancer in the next few years to come.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Limberger T et al. Mol Cancer 2022 Mar 30; 21(1):89.
Luo Y et al. Cancer Commun 2021 ;41(12):1427-1430.
Su X, Long Q et al. Prostate 2020 May; 80(6):508-517.
Dott. Gianfrancesco Cormaci
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