Alebady, Z.A.H.; Azizyan, M.; Nakjang, S.; Lishman-Walker, E.; Al-Kharaif, D.; Walker, S.; Choo, H.X.; Garnham, R.; Scott, E.; Johnson, K.L.; Robson, C.N.; Coffey, K. CDC20 Is Regulated by the Histone Methyltransferase, KMT5A, in Castration-Resistant Prostate Cancer. Cancers2023, 15, 3597.
Alebady, Z.A.H.; Azizyan, M.; Nakjang, S.; Lishman-Walker, E.; Al-Kharaif, D.; Walker, S.; Choo, H.X.; Garnham, R.; Scott, E.; Johnson, K.L.; Robson, C.N.; Coffey, K. CDC20 Is Regulated by the Histone Methyltransferase, KMT5A, in Castration-Resistant Prostate Cancer. Cancers 2023, 15, 3597.
Alebady, Z.A.H.; Azizyan, M.; Nakjang, S.; Lishman-Walker, E.; Al-Kharaif, D.; Walker, S.; Choo, H.X.; Garnham, R.; Scott, E.; Johnson, K.L.; Robson, C.N.; Coffey, K. CDC20 Is Regulated by the Histone Methyltransferase, KMT5A, in Castration-Resistant Prostate Cancer. Cancers2023, 15, 3597.
Alebady, Z.A.H.; Azizyan, M.; Nakjang, S.; Lishman-Walker, E.; Al-Kharaif, D.; Walker, S.; Choo, H.X.; Garnham, R.; Scott, E.; Johnson, K.L.; Robson, C.N.; Coffey, K. CDC20 Is Regulated by the Histone Methyltransferase, KMT5A, in Castration-Resistant Prostate Cancer. Cancers 2023, 15, 3597.
Abstract
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 in a prostate cancer cell line model of androgen independence following KMT5A knockdown in the presence of 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 apoptosis and DNA damage signaling are 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 both 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 utilized as a biomarker for effective therapeutic targeting.
Keywords
CDC20; BIOMARKER; KMT5A; p53; prostate cancer
Subject
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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