Bidirectional role of KLF5 in prostatic epithelial homeostasis and tumorigenesis

KLF5 在前列腺上皮稳态和肿瘤发生中的双向作用

• 批准号: 8842945
• 负责人: JIN-TANG DONG
• 金额: $ 32.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842945
• 关键词: Acetylation; Address; Adult; Affect; Biological Markers; Cancer Etiology; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Cessation of life; ChIP-seq; Chromosome Deletion; Complex; Deacetylation; Detection; Disease; Down-Regulation; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Equilibrium; Event; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Growth; Growth Factor; Health; Homeostasis; Human; Intestines; Knock-out; Knockout Mice; Knowledge; Lead; Literature; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Molecular; Molecular Abnormality; Molecular Profiling; Mus; Mutation; Neurosecretory Systems; Oncogenic; Paper; Prevention; Preventive; Process; Prognostic Factor; Proliferating; Prostate; Prostate carcinoma; Prostatic; Prostatic Neoplasms; Publishing; Role; Signal Transduction; Stem cells; Testing; Therapeutic Agents; Tissues; Tumor Promoters; Tumor Suppression; Tumor Suppressor Proteins; Up-Regulation; Work; Xenograft Model; adipocyte differentiation; base; cancer cell; cell type; improved; in vitro Model; in vivo; innovation; men; mouse model; mutant; novel; prostate cancer cell; protein degradation; therapeutic target; transcription factor; tumor; tumor initiation; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Summary: KLF5 is a basic transcription factor abundantly expressed in epithelial cells. It has a bidirectional role in cell proliferation control both promoting and inhibiting cell proliferation even in the same cells depending on growth factors. Whether and how such a bidirectional role occurs in vivo is unknown. KLF5 also has opposing functions in tumorigenesis, possessing both tumor suppressive and tumor promoter activities. How KLF5 executes opposing functions in tumorigenesis is another important question to address. In exploring how KLF5 functions in an unusual opposite manner, we found that in an in-vitro model of epithelial homeostasis, KLF5 is unacetylated and pro-proliferative without TGF-¿, but becomes acetylated to inhibit cell proliferation when TGF-¿ is present. The mechanism for this functional switch is that the unacetylated pro-proliferative KLF5 transcriptional complex is reassembled upon TGF-¿-induced KLF5 acetylation to alter gene regulation and cell proliferation control. In human tumors, Ac-KLF5 is downregulated and unAc-KLF5 is upregulated. We thus hypothesize that during epithelial homeostasis in adult prostates, KLF5 has a dual role that is determined by its acetylation status. Without differentiation signal, KLF5 is unacetylated and essential for progenitor cells to proliferate. When differentiation signal is activated, KLF5 becomes acetylated to alter gene transcription and initiate cell differentiation Insufficiency and deficiency of KLF5 acetylation disrupt cell differentiation and epithelial homeostasis, causing prostate cancer. We plan to test this hypothesis in three specific aims. (1) Expression of Klf5 in different types of cells and its bidirectional role in epithelial homeostasisin the prostate. Histological and molecular approaches will be applied to normal and genetically modified mice to examine Klf5 expression in different types of prostatic epithelial cells and address whether insufficiency (knockout) and deficiency (knockin) in Klf5 acetylation disrupt both proliferation and differentiation. (2) Opposite functions of Klf5 in prostate tumor initiation and progression. Klf5 will be knocked out in prostate epithelial cells. It will also be replaced wih acetylation-deficient Klf5K358R mutant (knockin). We will then test whether insufficiency (knockout) and deficiency (knockin) in Klf5 acetylation impair and abolish respectively Klf5's tumor suppressor function. Acetylation deficiency will be also tested in xenograft models of human prostate cancer. (3) How KLF5 executes opposing functions in epithelial homeostasis and tumorigenesis. Expression profiling combined with ChIP-Seq will be conducted to identify genes and gene signatures that are associated with KLF5's bidirectional function and acetylated and unacetylated KLF5. Such gene signatures will be compared with those of TGF-¿ and Pten from literature to evaluate their interactions with KLF5. We will also test whether and how excess growth signaling interferes with the acetylation of KLF5 when KLF5 is not deleted, which could lead to deacetylation of KLF5 and thus make KLF5 oncogenic. Genes mediating KLF5's oncogenic function have the potential to become biomarkers and therapeutic targets.

描述（应用程序提供）：摘要：KLF5是在上皮细胞中绝对表达的基本转录因子。它在细胞增殖控制中具有双向作用，即使在同一细胞中，根据生长因子，促进和抑制细胞增殖。这种双向角色是否在体内是否出现。 KLF5在肿瘤发生中也具有相反的功能，具有肿瘤抑制和肿瘤启动子活性。 KLF5如何在肿瘤发生中执行相反的功能是要解决的另一个重要问题。在探索KLF5如何以异常相反的方式发挥作用时，我们发现在上皮稳态的体外模型中，KLF5是不乙酰化的，并且在没有TGF- - 的情况下促成促生化，但在存在TGF-时会抑制细胞的乙酰基抑制细胞的增殖。该功能开关的机制是，在TGF-诱导的KLF5乙酰化以改变基因调节和细胞增殖对照时，将未乙酰化的促二酰化KLF5转录复合物重新组装。在人类肿瘤中，AC-KLF5被下调，UNAC-KLF5更新。因此，我们假设在成年前列腺上皮稳态期间，KLF5具有双重作用，由其乙酰化状态确定。没有分化信号，KLF5是未乙酰化的，对于祖细胞增殖至关重要。分化信号时 被激活，KLF5被乙酰化以改变基因转录并引发细胞分化的不足和KLF5乙酰化的缺乏破坏细胞分化和上皮稳态，从而导致前列腺癌。我们计划以三个具体目标来检验这一假设。 （1）KLF5在不同类型的细胞中的表达及其在前列腺上皮稳态中的双向作用。组织学和分子方法将应用于正常和一般修饰的小鼠，以检查不同类型的前列腺上皮细胞中的KLF5表达，并解决KLF5乙酰化中的不足（基因敲除）和缺乏症（敲除）是否破坏了增殖和差异。 （2）KLF5在前列腺肿瘤起源中的相反功能 和进展。 KLF5将在前列腺上皮细胞中被淘汰。它也将被缺乏乙酰化的KLF5K358R突变体（Knockin）取代。然后，我们将测试KLF5乙酰化的功能不全（基因敲除）和缺乏症（敲除）是否会损害和废除KLF5的肿瘤抑制功能。乙酰化缺乏症也将在人类前列腺癌的谱学模型中进行测试。 （3）KLF5如何在上皮稳态和肿瘤发生中执行相反的功能。将进行与CHIP-SEQ结合的表达分析，以识别与KLF5的双向功能以及乙酰化和未乙酰化KLF5相关的基因和基因特征。将这种基因的特征与TGF- - 和文献中的PTEN的特征进行比较，以评估其与KLF5的相互作用。当未删除KLF5时，我们还将测试以及如何超过生长信号传导干扰KLF5的乙酰化，这可能导致KLF5的脱乙酰基化，从而使KLF5致癌性。介导KLF5致癌功能的基因具有成为生物标志物和治疗靶标的潜力。