Keywords

1. KMT9 enzyme
2. Histone H4K12 methylation
3. Prostate cancer proliferation
4. Chromatin regulation
5. Castration-resistant prostate cancer treatment

A recent landmark discovery made by a consortium of medical researchers has revealed new insights into the ongoing battle against prostate cancer, offering hope for novel therapeutic avenues. This major scientific breakthrough, made by an international team led by researchers at the Albert-Ludwigs-Universität Freiburg, revolves around a previously unidentified enzyme, KMT9, which has been found to play a pivotal role in the proliferation of prostate cancer cells. This enzyme’s effect on histone modification is shedding light on new strategies to combat the progression of this disease, particularly in its more resilient forms.

Published in the prestigious journal Nature Structural & Molecular Biology, the paper titled “KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells” (DOI: 10.1038/s41594-019-0219-9) has drawn significant attention in the scientific community for its in-depth analysis and potential clinical implications. The study elucidates the intricate mechanisms by which the KMT9 enzyme, through the methylation of histone H4 on lysine 12 (H4K12), regulates gene expression and influences the growth of cancerous cells.

Histone lysine methylation is an epigenetic modification known to impact chromatin structure and gene transcription. Histone methylation involves the addition of methyl groups to the lysine residues of histone proteins by methyltransferase enzymes. The study’s primary focus, human C21orf127, also known as HEMK2, N6AMT1, or PrmC, was identified as a key player in this biological process. C21orf127 operates as an obligatory partner with another protein, TRMT112, to specifically target H4K12. Together this complex, newly termed ‘lysine methyltransferase 9’ or KMT9, writes methylation marks instrumental for cellular function.

The research team, spearheaded by lead authors Eric Metzger and Sheng Wang of the Albert-Ludwigs-Universität Freiburg, carried out a series of comprehensive experiments. These included crystal structure analysis of human C21orf127-TRMT112 in complex with S-adenosyl-homocysteine and a peptide of H4K12me1, which revealed how KMT9 precisely recognizes and methylates histone H4K12.

Furthermore, global profiling indicated that KMT9 and the H4K12me1 mark are enriched near the promoters of an array of genes connected to cell cycle regulation. This enrichment suggests that KMT9 has a widespread impact on the genome’s transcriptional landscape, particularly influencing genes that are critical for controlling cell division. Through meticulous gene expression analyses, the researchers provided evidence that KMT9 directly modulates the proliferation of cells.

The significance of this discovery becomes particularly pronounced in the context of androgen receptor-dependent prostate cancer cells, including those that have developed resistance to conventional treatments such as castration or the drug enzalutamide. The depletion of KMT9 in these cells, as demonstrated in the study, leads to markedly impaired cancerous cell proliferation and impedes the growth of xenograft tumors.

This novel understanding of KMT9’s role is important not only for elucidating fundamental biological mechanisms but also for its clinical oncology implications. Prostate cancer, being one of the most common cancers among men worldwide, poses a significant challenge in its advanced stages, especially once it becomes resistant to hormone therapy—a condition known as castration-resistant prostate cancer (CRPC). The current research on KMT9 opens up the possibility for new therapeutic strategies aimed at targeting this enzyme to inhibit the growth of CRPC cells.

The team involved in this project has cast a wide interdisciplinary net, encompassing professionals from the Klinikum der Albert-Ludwigs-Universität Freiburg, Ludwig-Maximilians-University of Munich, the University Hospital Basel, the University of Schleswig-Holstein, and the Albert-Ludwigs-Universität Freiburg itself.

As Roland Schüle, the senior author, emphasizes, “The identification of KMT9’s activity and its impact on prostate cancer cell proliferation is a major step forward in our understanding of this disease. Our findings lay the groundwork for the development of novel therapeutic agents that could selectively inhibit KMT9, offering new hope for patients suffering from advanced and treatment-resistant prostate cancer.”

This research rises as a starting point for the medical and scientific community to develop potential inhibitors of KMT9 as a therapeutic strategy. Given the profound implications of histone modifications on cancer development and the specificity of KMT9’s enzymatic activity, the targeted inhibition of this enzyme could become a cornerstone in the fight against CRPC.

The research, bolstered by support from the Deutsches Konsortium für Translationale Krebsforschung and other notable institutions, serves to further our arsenal against one of the most challenging variants of prostate cancer. With continued exploration and potential future clinical trials, the insights from the study may soon transition from bench to bedside, offering tangible benefits in terms of improved patient outcomes.

In conclusion, the discovery of KMT9’s role in histone H4K12 methylation and its subsequent control of prostate cancer cell proliferation is a scientific advancement with promising therapeutic ramifications. This research not only deepens our comprehension of the epigenetic intricacies involved in cancer progression but also fuels the development of targeted treatments for CRPC, increasing the potential for improved management and survival rates for patients facing this aggressive disease.

References

1. Metzger, E., Wang, S., Urban, S., Willmann, D., Schmidt, A., Offermann, A., … Schüle, R. (2019). KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells. Nature Structural & Molecular Biology, 26(5), 361-371. DOI: 10.1038/s41594-019-0219-9

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