The Effect Of KAT8 On The Resistance Of Castration Resistant Prostate Cancer To Enzalutamide

Prostate cancer is the second leading cause of cancer-related death in men after lung cancer.Given the important role of the Androgen Receptor(AR)signalling pathway in primary prostate cancer,androgen deprivation therapy is the treatment of choice for most patients.Androgen deprivation therapy is effective in the early stages of cancer,but after an average of 2 years of androgen deprivation therapy,patients usually progress from Castration-Sensitive Prostate Cancer(CSPC)to CastrationResistant Prostate Cancer(CRPC).Enzalutamide,an AR pathway inhibitor,has been used to treat CRPC in response to the fact that patients with CRPC are no longer sensitive to androgen deprivation therapy.Although Enzalutamide has some inhibitory effect on CRPC,patients subsequently develop resistance to Enzalutamide due to a number of mechanisms.For example,reactivation of the AR signalling pathway in Enzalutamide resistant CRPC and the emergence of constitutively activated androgen receptor variant 7(AR Variants-7,AR-V7).In recent years,an increasing number of studies have used post-translational modifications of proteins to address tumour resistance and a variety of drugs targeting post-translational modifications of proteins have been used to overcome tumour resistance.Lysine acetyltransferase 8(KAT8),also known as MOF or MYST1,has the primary role of acetylating H4K16.In addition,KAT8 can also acetylate non-histone proteins,including TP53 and IL33.It has been demonstrated that acetylation of AR/ARV7 affects its modification by the ubiquitin-proteasome,thus acting to increase the stability of AR/AR-V7 proteins.Thus,acetyltransferases could play a significant role in the progression of CRPC and in the resistance of CRPC to Enzalutamide by regulating the protein stability of AR/AR-V7.However,the role of the acetyltransferase KAT8 in CRPC and its resistance to Enzalutamide has not been investigated.The present study used multiple databases to demonstrate that KAT8 expression is upregulated in CRPC tissues and could be a potential clinical prognostic indicator.Immunofluorescence as well as immunoprecipitation assays demonstrated a direct interaction between KAT8 and AR/AR-V7 in CRPC cells.Inhibition of KAT8 decreased the protein expression of AR/AR-V7.Immunoprecipitation assays show that inhibition of KAT8 decreases acetylation and increases ubiquitination of AR/AR-V7.CUL4B,the scaffolding protein of the E3 ubiquitin ligase complex CRL4B,is involved in the regulation of ubiquitination of AR/AR-V7 by KAT8,thereby affecting the protein stability of AR/AR-V7.Knockdown of KAT8 in CRPC cells inhibited the AR signalling pathway and down-regulated the transcription of genes downstream of this pathway.CCK8 and clone formation assays showed that inhibition of KAT8 increased the sensitivity of CRPC cells to Enzalutamide.The KAT8 inhibitor MG149 in combination with Enzalutamide significantly inhibited the growth of CRPC cells.In conclusion,lysine acetyltransferase KAT8 activates the AR signaling pathway by increasing the protein stability of AR/AR-V7 in CRPC,thereby increasing the resistance of CRPC to Enzalutamide.