Increased MYBL2 expression in aggressive hormone-sensitive prostate cancer.
Increased MYBL2 expression in aggressive hormone-sensitive prostate cancer.
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DOI：
10.1002/1878-0261.13314
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发表时间：
2022-12
影响因子：
6.6
通讯作者：
Sweeney, Christopher J.
中科院分区：
文献类型：
--
作者：
Yoshikawa, Yuki;Stopsack, Konrad H.;Wang, Xin Victoria;Chen, Yu-Hui;Mazzu, Ying Z.;Burton, Foster;Chakraborty, Goutam;Rajanala, Sai Harisha;Hirani, Rahim;Nandakumar, Subhiksha;Lee, Gwo-Shu Mary;Frank, David;Davicioni, Elai;Liu, Glenn;Carducci, Michael A.;Azuma, Haruhito;Kantoff, Philip W.;Sweeney, Christopher J.
组蛋白去甲基化酶KDM5D（赖氨酸特异性去甲基化酶5D）的缺失导致前列腺癌细胞对雄激素剥夺疗法（ADT）（有或无多西他赛）的体外耐药性。我们的目标是定义KDM5D效应的下游驱动因素。使用染色质免疫沉淀测序（ChIP‐seq）对具有和不具有沉默的KDM5D的LNCaP细胞系（雄激素敏感性人前列腺癌）进行分析，MYBL 2结合位点。在患有局限性和转移性激素敏感性前列腺癌的男性队列中评估MYBL 2 mRNA表达与临床结局之间的关联。在雄激素受体（AR）阳性激素敏感性前列腺癌细胞系LNCaP和LAPC 4中进行MYBL 2和KDM 5D沉默和过表达的体外试验，以评估其对细胞增殖、凋亡和细胞周期分布的影响，以及对雄激素剥夺、多西他赛和卡巴他赛的敏感性。我们发现沉默KDM5D增加组蛋白H3赖氨酸K4（H3K4）三甲基化并增加MYBL 2表达。KDM5D和MYBL 2与部分但非全部临床样本呈负相关。在CHAARTED试验中，较高的MYBL 2表达与局部疾病的较高复发率和转移性疾病男性的较差总生存率相关。较低的MYBL 2水平增强了LNCaP和LAPC 4对雄激素剥夺和紫杉烷的敏感性。在体外，KDM5D和MYBL 2的修饰以细胞系特异性方式改变了细胞周期分布和凋亡。这些结果表明，转录因子MYBL 2影响体外激素敏感性前列腺癌对雄激素剥夺和紫杉烷的敏感性，并且较低的水平与患有激素敏感性前列腺癌的男性的更好的临床结果相关。较高水平的转录因子MYBL 2增加了侵袭性，并降低了激素敏感性前列腺癌对雄激素剥夺和多西他赛的敏感性。
Loss of the histone demethylase KDM5D (lysine‐specific demethylase 5D) leads to in vitro resistance of prostate cancer cells to androgen deprivation therapy (ADT) with and without docetaxel. We aimed to define downstream drivers of the KDM5D effect. Using chromatin immunoprecipitation sequencing (ChIP‐seq) of the LNCaP cell line (androgen‐sensitive human prostate adenocarcinoma) with and without silenced KDM5D, MYBL2‐binding sites were analyzed. Associations between MYBL2 mRNA expression and clinical outcomes were assessed in cohorts of men with localized and metastatic hormone‐sensitive prostate cancer. In vitro assays with silencing and overexpression of MYBL2 and KDM5D in androgen receptor (AR)‐positive hormone‐sensitive prostate cancer cell lines, LNCaP and LAPC4, were used to assess their influence on cellular proliferation, apoptosis, and cell cycle distribution, as well as sensitivity to androgen deprivation, docetaxel, and cabazitaxel. We found that silencing KDM5D increased histone H3 lysine K4 (H3K4) trimethylation and increased MYBL2 expression. KDM5D and MYBL2 were negatively correlated with some but not all clinical samples. Higher MYBL2 expression was associated with a higher rate of relapse in localized disease and poorer overall survival in men with metastatic disease in the CHAARTED trial. Lower MYBL2 levels enhanced LNCaP and LAPC4 sensitivity to androgen deprivation and taxanes. In vitro, modifications of KDM5D and MYBL2 altered cell cycle distribution and apoptosis in a cell line‐specific manner. These results show that the transcription factor MYBL2 impacts in vitro hormone‐sensitive prostate cancer sensitivity to androgen deprivation and taxanes, and lower levels are associated with better clinical outcomes in men with hormone‐sensitive prostate cancer. Higher levels of the transcription factor MYBL2 increase the aggressiveness and decrease the sensitivity of hormone‐sensitive prostate cancer to androgen deprivation and docetaxel.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
23.4
作者：
Gravis G;Boher JM;Chen YH;Liu G;Fizazi K;Carducci MA;Oudard S;Joly F;Jarrard DM;Soulie M;Eisenberger MJ;Habibian M;Dreicer R;Garcia JA;Hussain MHM;Kohli M;Vogelzang NJ;Picus J;DiPaola R;Sweeney C
通讯作者：
Sweeney C
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
45.3
作者：
Kyriakopoulos, Christos E.;Chen, Yu-Hui;Sweeney, Christopher J.
通讯作者：
Sweeney, Christopher J.
影响因子：
23.4
作者：
Humid, Anis A.;Gray, Kathryn P.;Sweeney, Christopher J.
通讯作者：
Sweeney, Christopher J.