Alebady Zainab A H, Azizyan Mahsa, Nakjang Sirintra, Lishman-Walker Emma, Al-Kharaif Dhuha, Walker Scott, Choo Hui Xian, Garnham Rebecca, Scott Emma, Johnson Katya L, Robson Craig N, Coffey Kelly
Biosciences Institute, Newcastle Cancer Centre, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Department of Laboratory and Clinical Science, College of Pharmacy, University of AL-Qadisiyah, Al-Diwaniya 58002, Iraq.
Cancers (Basel). 2023 Jul 13;15(14):3597. doi: 10.3390/cancers15143597.
The methyltransferase KMT5A has been proposed as an oncogene in prostate cancer and therefore represents a putative therapeutic target. To confirm this hypothesis, we have performed a microarray study on a prostate cancer cell line model of androgen independence following KMT5A knockdown in the presence of the transcriptionally active androgen receptor (AR) to understand which genes and cellular processes are regulated by KMT5A in the presence of an active AR. We observed that 301 genes were down-regulated whilst 408 were up-regulated when KMT5A expression was reduced. KEGG pathway and gene ontology analysis revealed that apoptosis and DNA damage signalling were up-regulated in response to KMT5A knockdown whilst protein folding and RNA splicing were down-regulated. Under these conditions, the top non-AR regulated gene was found to be CDC20, a key regulator of the spindle assembly checkpoint with an oncogenic role in several cancer types. Further investigation revealed that KMT5A regulates CDC20 in a methyltransferase-dependent manner to modulate histone H4K20 methylation within its promoter region and indirectly via the p53 signalling pathway. A positive correlation between KMT5A and CDC20 expression was also observed in clinical prostate cancer samples, further supporting this association. Therefore, we conclude that KMT5A is a valid therapeutic target for the treatment of prostate cancer and CDC20 could potentially be utilised as a biomarker for effective therapeutic targeting.
甲基转移酶KMT5A已被提出作为前列腺癌中的一种癌基因，因此是一个假定的治疗靶点。为了证实这一假设，我们在存在转录活性雄激素受体（AR）的情况下，对KMT5A敲低后的雄激素非依赖性前列腺癌细胞系模型进行了微阵列研究，以了解在活性AR存在的情况下，哪些基因和细胞过程受KMT5A调控。我们观察到，当KMT5A表达降低时，301个基因下调，408个基因上调。KEGG通路和基因本体分析显示，响应KMT5A敲低，细胞凋亡和DNA损伤信号上调，而蛋白质折叠和RNA剪接下调。在这些条件下，发现排名最靠前的非AR调控基因是CDC20，它是纺锤体组装检查点的关键调节因子，在几种癌症类型中具有致癌作用。进一步研究表明，KMT5A以甲基转移酶依赖性方式调节CDC20，以调节其启动子区域内的组蛋白H4K20甲基化，并间接通过p53信号通路进行调节。在临床前列腺癌样本中也观察到KMT5A和CDC20表达之间呈正相关，进一步支持了这种关联。因此，我们得出结论，KMT5A是治疗前列腺癌的有效治疗靶点，并可能将CDC20用作有效治疗靶向的生物标志物。
