Mechanism and role of aberrant AR activity in castration-resistant prostate cancer

异常 AR 活性在去势抵抗性前列腺癌中的机制和作用

基本信息

  • 批准号:
    10328915
  • 负责人:
  • 金额:
    $ 35.64万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-02-05 至 2023-12-05
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Castration-resistant prostate cancer (CRPC) is the major cause of prostate cancer (PCa) mortality. Targeting the androgens-androgen receptor (AR) axis by the second-generation endocrine therapies such as abiraterone (ABI) and enzalutamide (ENZ) has been effective initially for CRPC treatment in clinic. However, most patients develop resistance that undermines survival and quality of life and the therapy resistance is likely due to expression of AR splice variants (AR-Vs) such as AR-V7 and/or other undefined mechanisms. Prostate- specific antigen (PSA or known as KLK3) is one of the genes that are highly transcriptionally activated by AR. Despite being extensively utilized as a biomarker for PCa diagnosis and prognosis, the significance of the PSA gene or the entire genomic locus of this gene in PCa growth and survival has yet been well established. We demonstrated that non-coding RNA transcribed from the PSA enhancer, or called PSA eRNA, is aberrantly upregulated in CRPC cells in culture, xenografts and patient tissues. We further showed that expression of PSA eRNA is regulated by AR-Vs in ENZ-resistant CRPC cells. Moreover, we showed that PSA eRNA has cis-effects on PSA mRNA expression as well as broad trans-effects on expression of AR-regulated biologically important genes in CRPC cells. Mechanistically, we found that PSA eRNA contains a HIV-1 TAR RNA like (TAR-L) motif that is crucial for binding to CYCLIN T1, a key component of the positive transcription elongation factor b (P-TEFb) complex and P-TEFb-mediated RNA polymerase II serine 2 phosphorylation (Pol II-Ser2p). Importantly, we demonstrated that targeting PSA eRNA with generation 2.5 antisense oligonucleotides (ASOs) inhibits growth of ENZ-resistant CRPC cells. Our further studies showed that eRNA transcribed from the FTO gene enhancer, one of the AR-eRNAs induced by ENZ, binds to RNA splicing factors and regulates expression of AR splice variant AR-V7 in ENZ-resistant CRPC cells. These findings support the hypothesis that aberrant expression of AR-eRNAs including PSA and FTO eRNAs acts as a new proxy of AR functional abnormality that promotes endocrine therapy-resistant growth of CRPC, thereby representing a novel target for CRPC treatment. In this application, we will determine the mechanisms by which PSA eRNA regulates gene transcription and FTO eRNA regulates AR-V7 expression in ENZ-resistant CRPC cells (Aim 1) and to determine the functional importance and clinical significance of PSA eRNA expression in ENZ- and ABI- resistant CRPC cells using mouse models and human patient samples (Aim 2). These studies will employ a comprehensive approach bringing complementary expertise in tumor biology, molecular biology, medical oncology, pathobiology, computing science and bioinformatics and biomedical statistics. Findings from the proposed studies will significantly advance our understanding of the mechanisms that drives aberrant AR activity and therapy-resistant growth of CRPC cells, but also allow us to develop new strategies by targeting PSA eRNA to inhibit aberrant AR activity for effective treatment of CRPC.
项目概要 去势抵抗性前列腺癌(CRPC)是前列腺癌(PCa)死亡的主要原因。瞄准 第二代内分泌疗法(如阿比特龙)的雄激素-雄激素受体(AR)轴 (ABI)和恩杂鲁胺(ENZ)在临床上对CRPC治疗已初步有效。然而,大多数患者 产生损害生存和生活质量的耐药性,治疗耐药性可能是由于 AR 剪接变体 (AR-V) 的表达,例如 AR-V7 和/或其他未定义的机制。前列腺- 特异性抗原(PSA 或称为 KLK3)是 AR 高度转录激活的基因之一。 尽管 PSA 被广泛用作 PCa 诊断和预后的生物标志物,但其重要性 基因或该基因的整个基因组位点在 PCa 生长和存活中的作用尚未明确。我们 证明从 PSA 增强子转录的非编码 RNA,或称为 PSA eRNA,是异常的 在培养物、异种移植物和患者组织中的 CRPC 细胞中上调。我们进一步证明了表达式 在 ENZ 抗性 CRPC 细胞中,PSA eRNA 受 AR-V 调节。此外,我们还发现 PSA eRNA 对 PSA mRNA 表达的顺式效应以及对 AR 生物调节表达的广泛反式效应 CRPC 细胞中的重要基因。从机制上讲,我们发现 PSA eRNA 包含类似 HIV-1 TAR RNA (TAR-L) 基序对于结合 CYCLIN T1 至关重要,CYCLIN T1 是正转录延伸的关键组成部分 b 因子 (P-TEFb) 复合物和 P-TEFb 介导的 RNA 聚合酶 II 丝氨酸 2 磷酸化 (Pol II-Ser2p)。 重要的是,我们证明了使用 2.5 代反义寡核苷酸 (ASO) 靶向 PSA eRNA 抑制 ENZ 耐药 CRPC 细胞的生长。我们进一步的研究表明,eRNA 是从 FTO 转录而来的。 基因增强子是 ENZ 诱导的 AR-eRNA 之一,与 RNA 剪接因子结合并调节表达 AR 剪接变体 AR-V7 在 ENZ 抗性 CRPC 细胞中的作用。这些发现支持了以下假设:异常 AR-eRNA(包括 PSA 和 FTO eRNA)的表达作为 AR 功能异常的新指标 促进内分泌治疗耐药的 CRPC 生长,从而代表 CRPC 的新靶点 治疗。在此应用中,我们将确定 PSA eRNA 调节基因的机制 转录和 FTO eRNA 调节 ENZ 抗性 CRPC 细胞中的 AR-V7 表达(目标 1)并 确定 ENZ- 和 ABI- 中 PSA eRNA 表达的功能重要性和临床意义 使用小鼠模型和人类患者样本研究耐药 CRPC 细胞(目标 2)。这些研究将采用 综合方法带来肿瘤生物学、分子生物学、医学方面的互补专业知识 肿瘤学、病理学、计算科学以及生物信息学和生物医学统计学。调查结果来自 拟议的研究将显着增进我们对驱动异常 AR 机制的理解 CRPC 细胞的活性和治疗抗性生长,但也使我们能够通过靶向开发新策略 PSA eRNA 抑制异常 AR 活性,有效治疗 CRPC。

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A lncRNA from the FTO locus acts as a suppressor of the m6A writer complex and p53 tumor suppression signaling.
来自 FTO 位点的 lncRNA 充当 m6A writer 复合物和 p53 肿瘤抑制信号传导的抑制剂。
  • DOI:
    10.1016/j.molcel.2023.06.024
  • 发表时间:
    2023-07-01
  • 期刊:
  • 影响因子:
    16
  • 作者:
    Jianong Zhang;Jiangbo W;Rui Sun;Haoyue Sheng;Kai Yin;Yunqian Pan;Rafael Jiménez;Sujun Chen;X. Cui;Zhongyu Zou;Zhiying Yue;M. Emch;J. Hawse;Liguo Wang;H. He;Shujie Xia;B. Han;C. He;Haojie Huang
  • 通讯作者:
    Haojie Huang
Overcoming EZH2 Inhibitor Resistance by Taxane in PTEN-Mutated Cancer.
通过紫杉烷克服 PTEN 突变癌症中的 EZH2 抑制剂耐药性。
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    12.4
  • 作者:
    Ma, Linlin;Yan, Yuqian;Bai, Yang;Yang, Yinhui;Pan, Yunqian;Gang, Xiaokun;Karnes, R Jeffrey;Zhang, Jun;Lv, Qiubo;Wu, Qiang;Huang, Haojie
  • 通讯作者:
    Huang, Haojie
Lineage plasticity-mediated therapy resistance in prostate cancer.
前列腺癌中谱系可塑性介导的治疗耐药性。
  • DOI:
  • 发表时间:
    2019-05
  • 期刊:
  • 影响因子:
    2.9
  • 作者:
    Blee, Alexandra M;Huang, Haojie
  • 通讯作者:
    Huang, Haojie
RUNX2 overexpression and PTEN haploinsufficiency cooperate to promote CXCR7 expression and cellular trafficking, AKT hyperactivation and prostate tumorigenesis.
RUNX2 过表达和 PTEN 单倍体不足共同促进 CXCR7 表达和细胞运输、AKT 过度激活和前列腺肿瘤发生。
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    12.4
  • 作者:
    Bai, Yang;Yang, Yinhui;Yan, Yuqian;Zhong, Jian;Blee, Alexandra M;Pan, Yunqian;Ma, Tao;Karnes, R Jeffrey;Jimenez, Rafael;Xu, Wanhai;Huang, Haojie
  • 通讯作者:
    Huang, Haojie
ATM-phosphorylated SPOP contributes to 53BP1 exclusion from chromatin during DNA replication.
ATM 磷酸化 SPOP 有助于在 DNA 复制过程中将 53BP1 排除在染色质之外。
  • DOI:
  • 发表时间:
    2021-06
  • 期刊:
  • 影响因子:
    13.6
  • 作者:
    Wang, Dejie;Ma, Jian;Botuyan, Maria Victoria;Cui, Gaofeng;Yan, Yuqian;Ding, Donglin;Zhou, Yingke;Krueger, Eugene W;Pei, Jiang;Wu, Xiaosheng;Wang, Liguo;Pei, Huadong;McNiven, Mark A;Ye, Dingwei;Mer, Georges;Huang, Haojie
  • 通讯作者:
    Huang, Haojie
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Haojie Huang其他文献

Haojie Huang的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Haojie Huang', 18)}}的其他基金

Mechanism and role of aberrant AR activity in castration-resistant prostate cancer
异常 AR 活性在去势抵抗性前列腺癌中的机制和作用
  • 批准号:
    10082434
  • 财政年份:
    2018
  • 资助金额:
    $ 35.64万
  • 项目类别:
Role of RUNX2 in prostate cancer intratumoral androgen synthesis and progression
RUNX2在前列腺癌瘤内雄激素合成和进展中的作用
  • 批准号:
    9026029
  • 财政年份:
    2015
  • 资助金额:
    $ 35.64万
  • 项目类别:
Role of RUNX2 in prostate cancer intratumoral androgen synthesis and progression
RUNX2在前列腺癌瘤内雄激素合成和进展中的作用
  • 批准号:
    9537435
  • 财政年份:
    2015
  • 资助金额:
    $ 35.64万
  • 项目类别:
Role of RUNX2 in prostate cancer intratumoral androgen synthesis and progression
RUNX2在前列腺癌瘤内雄激素合成和进展中的作用
  • 批准号:
    9330092
  • 财政年份:
    2015
  • 资助金额:
    $ 35.64万
  • 项目类别:
Role of proinflammatory cytokine-induced AR degradation in castration-resistant prostate cancer
促炎细胞因子诱导的 AR 降解在去势抵抗性前列腺癌中的作用
  • 批准号:
    9395337
  • 财政年份:
    2010
  • 资助金额:
    $ 35.64万
  • 项目类别:
Mechanism of promiscuous AR activation in PTEN-mutated prostate cancer
PTEN突变前列腺癌中AR混杂激活的机制
  • 批准号:
    8676688
  • 财政年份:
    2010
  • 资助金额:
    $ 35.64万
  • 项目类别:
Role of proinflammatory cytokine-induced AR degradation in castration-resistant prostate cancer
促炎细胞因子诱导的 AR 降解在去势抵抗性前列腺癌中的作用
  • 批准号:
    10189524
  • 财政年份:
    2010
  • 资助金额:
    $ 35.64万
  • 项目类别:
Mechanism of promiscuous AR activation in PTEN-mutated prostate cancer
PTEN突变前列腺癌中AR混杂激活的机制
  • 批准号:
    8212862
  • 财政年份:
    2010
  • 资助金额:
    $ 35.64万
  • 项目类别:
Mechanism of promiscuous AR activation in PTEN-mutated prostate cancer
PTEN突变前列腺癌中AR混杂激活的机制
  • 批准号:
    8468656
  • 财政年份:
    2010
  • 资助金额:
    $ 35.64万
  • 项目类别:
Mechanism of promiscuous AR activation in PTEN-mutated prostate cancer
PTEN突变前列腺癌中AR混杂激活的机制
  • 批准号:
    8853827
  • 财政年份:
    2010
  • 资助金额:
    $ 35.64万
  • 项目类别:

相似海外基金

Modulating HSP70/STUB1 machinery in therapy-resistant prostate cancer
调节 HSP70/STUB1 机制治疗耐药性前列腺癌
  • 批准号:
    10442601
  • 财政年份:
    2021
  • 资助金额:
    $ 35.64万
  • 项目类别:
Modulating HSP70/STUB1 machinery in therapy-resistant prostate cancer
调节 HSP70/STUB1 机制治疗耐药性前列腺癌
  • 批准号:
    10298903
  • 财政年份:
    2021
  • 资助金额:
    $ 35.64万
  • 项目类别:
Modulating HSP70/STUB1 machinery in therapy-resistant prostate cancer
调节 HSP70/STUB1 机制治疗耐药性前列腺癌
  • 批准号:
    10678891
  • 财政年份:
    2021
  • 资助金额:
    $ 35.64万
  • 项目类别:
Modulating HSP70/STUB1 machinery in therapy-resistant prostate cancer
调节 HSP70/STUB1 机制治疗耐药性前列腺癌
  • 批准号:
    10298903
  • 财政年份:
    2021
  • 资助金额:
    $ 35.64万
  • 项目类别:
Elucidating Synergy of Enzalutamide and Src Kinase Inhibitors in Castration-Resistant Prostate Cancer
阐明恩杂鲁胺和 Src 激酶抑制剂在去势抵抗性前列腺癌中的协同作用
  • 批准号:
    10476997
  • 财政年份:
    2021
  • 资助金额:
    $ 35.64万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了