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We thank M. Timmers for providing T24 cells, S. Garczyk for providing RT-112 and J82 cells, and E. Pitt for providing TCC-SUP-G and JON cells. We also thank T. Reinheckel for providing NOD SCID mice. Biological materials were purchased from the Ontario Tumour Bank, which is supported by the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. We are grateful for the charitable contributions of G. Rockstroh.

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Lysine Methyltransferase 9 (KMT9) Is an Actionable Target in Muscle-Invasive Bladder Cancer

Publicated to:Cancers. 16 (8): 1532- - 2024-04-01 16(8), DOI: 10.3390/cancers16081532

Authors: Totonji, Sainab; Ramos-Triguero, Anna; Willmann, Dominica; Sum, Manuela; Urban, Sylvia; Bauer, Helena; Rieder, Astrid; Wang, Sheng; Greschik, Holger; Metzger, Eric; Schuele, Roland

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Abstract

Simple Summary The recently identified lysine methyltransferase (KMT) 9 regulates the growth of different types of cancer. While KMT9 was shown to be overexpressed in muscle-invasive bladder cancer (MIBC) tissue samples of patients, a potential functional role of the enzyme in MIBC remains to be clarified. In this study, we show that KMT9 regulates the proliferation, migration, and invasion of various MIBC cell lines as well as the growth of BC tumor organoids and xenografts in mice. Our data provide evidence that tumor cell growth relies on the enzymatic function of KMT9 and that a small-molecule inhibitor of KMT9 impairs BC cell proliferation. These results suggest that KMT9 is a potential novel therapeutic target for MIBC treatment.Abstract Novel treatment modalities are imperative for the challenging management of muscle-invasive and metastatic BC to improve patient survival rates. The recently identified KMT9, an obligate heterodimer composed of KMT9 alpha and KMT9 beta, regulates the growth of various types of tumors such as prostate, lung, and colon cancer. While the overexpression of KMT9 alpha was previously observed to be associated with aggressive basal-like MIBC in an analysis of patients' tissue samples, a potential functional role of KMT9 in this type of cancer has not been investigated to date. In this study, we show that KMT9 regulates proliferation, migration, and invasion of various MIBC cell lines with different genetic mutations. KMT9 alpha depletion results in the differential expression of genes regulating the cell cycle, cell adhesion, and migration. Differentially expressed genes include oncogenes such as EGFR and AKT1 as well as mediators of cell adhesion or migration such as DAG1 and ITGA6. Reduced cell proliferation upon KMT9 alpha depletion is also observed in Pten/Trp53 knockout bladder tumor organoids, which cannot be rescued with an enzymatically inactive KMT9 alpha mutant. In accordance with the idea that the catalytic activity of KMT9 is required for the control of cellular processes in MIBC, a recently developed small-molecule inhibitor of KMT9 (KMI169) also impairs cancer cell proliferation. Since KMT9 alpha depletion also restricts the growth of xenografts in mice, our data suggest that KMT9 is an actionable novel therapeutic target for the treatment of MIBC.

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