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需要p300/CBP降解来禁用前列腺癌中活跃的AR增强酶体

Jie Luo^1,2,3, Zhixiang Chen^4,5,6,3, Yuanyuan Qiao^1,2,3

¹Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.

bioRxiv : the preprint server for biology

|April 8, 2024

概括

通过激活雄激素受体增强酶,p300和CBP对于前列腺癌的进展至关重要. 降解这些蛋白质,而不是抑制它们,有效地抑制了瘤,并显示出治疗晚期前列腺癌的前景.

科学领域:

分子生物学分子生物学
癌症生物学癌症生物学
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.

背景情况:

前列腺癌是由转录因子驱动的,特别是雌激素受体 (AR) 增强体.
p300和CBP是关键的氨酸转移酶,参与增强剂激活.
基因组基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因.

研究的目的:

研究p300/CBP作为前列腺癌中AR增强体的决定性辅因子的作用.
为了比较p300/CBP降解与抑制对前列腺癌进展的影响.
在临床前模型中评估p300/CBP降解剂的治疗潜力.

主要方法:

评估了基因组H2B N端多位 lysine 乙化 (H2BNTac) 作为活性增强剂的标记物.
利用p300/CBP降解和odomain抑制来研究它们的影响.
在体内采用一种口服活性的p300/CBP蛋白质溶解向化母 (PROTAC) 降解剂 (CBPD-409).
评估瘤生长抑制和割耐药前列腺癌的临床前模型中的毒性.

主要成果:

在前列腺癌病变中,依赖p300/CBP催化功能的H2BNTac升高.
p300/CBP降解耗尽AR增强酶体乙化标志比odomain抑制更有效.
p300/CBP降解抑制了致癌基因程序,并在体内抑制了瘤生长.
在临床前模型中,PROTAC降解剂CBPD-409耐受性良好,并与AR抗剂协同作用.

结论:

p300/CBP对于维持前列腺癌中活跃的AR增强酶体至关重要.
针对p300/CBP的向降解,与抑制相比,具有明显而强大的治疗优势.
p300/CBP降解剂代表了晚期前列腺癌的有前途的治疗策略.

关键词:

美国中央银行 (CBP) 的CBP.雄激素受体增强酶体的作用基因组 H2BNTac 的使用.在P300上,P300是P300.p300/CBP降解剂可以降解前列腺癌是前列腺癌.

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