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 KMT9α and KMT9β, regulates the growth of various types of tumors such as prostate, lung, and colon cancer. While the overexpression of KMT9α 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. KMT9α 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 KMT9α depletion is also observed inPten/Trp53knockout bladder tumor organoids, which cannot be rescued with an enzymatically inactive KMT9α 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 KMT9α 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.
针对肌层浸润性和转移性膀胱癌（BC）的棘手治疗，亟需新的治疗策略以提高患者生存率。近期发现的KMT9是一种由KMT9α和KMT9β组成的专性异源二聚体，可调控前列腺癌、肺癌和结肠癌等多种肿瘤的生长。尽管先前对患者组织样本的分析发现KMT9α的过表达与侵袭性基底样肌层浸润性膀胱癌（MIBC）相关，但KMT9在此类癌症中的潜在功能作用至今尚未得到研究。本研究显示，KMT9调控具有不同基因突变的多种MIBC细胞系的增殖、迁移和侵袭能力。KMT9α缺失会导致调控细胞周期、细胞粘附和迁移的基因出现差异表达，这些差异表达基因包括EGFR和AKT1等癌基因，以及DAG1和ITGA6等细胞粘附或迁移介质。在Pten/Trp53基因敲除的膀胱肿瘤类器官中，同样观察到KMT9α缺失导致的细胞增殖减少，且这种效应无法通过酶活性缺失的KMT9α突变体挽救。与KMT9催化活性在调控MIBC细胞过程中不可或缺的观点一致，近期开发的小分子KMT9抑制剂（KMI169）同样能抑制癌细胞增殖。由于KMT9α缺失还能限制小鼠移植瘤的生长，我们的数据表明KMT9是治疗MIBC的一个可行新型治疗靶点。
Lysine Methyltransferase 9 (KMT9) Is an Actionable Target in Muscle-Invasive Bladder Cancer
肿瘤(癌症)患者之家