The PI3K/AKT Pathway Regulates Histone H3 Modification

项目总结 PI3K/AKT通路激活，最常见的发生通过PIK3CA突变或PTEN失活， 放松对细胞生长、新陈代谢和细胞存活的管制，是人类癌症中常见的重大事件。 现在的研究表明，癌症既是一种遗传性疾病，也是一种表观遗传性疾病，因为染色质的变化 景观频繁出现。高水平的H3K4me3标记，表明转录能力 在某些癌症类型中与预后不良有关。H3K4组蛋白去甲基酶KDM5A可能介导 在PI3K突变的癌症中，一种对EGFR抑制反应的耐药状态。此外，AKT之前是 显示通过H3K27甲基转移酶EZH2的磷酸化减少H3K27me3。因此，我 研究了PI3K/AKT是否调节转录能力。我的初步研究和第一，第一- 我博士后研究的作者手稿表明，AKT通过直接促进细胞生长 调节KDM5A，增加H3K4me3。这些数据为我未来的研究目标提供了基础 如下所述。 我直接的职业目标是在道德上进行高质量的科学研究，并在一流水平上发表我的研究成果， 同行评议的杂志，这样我就可以成为染色质交叉点的独立研究员 生物学和致癌信号。我直接的研究目标100%体现在研究中 我为K99/R00提出的计划。在这项建议中，我计划首先制定一个全面的 了解致癌的PI3K/AKT如何促进H3K4me3(目标1)。因为H3K4me3已经被 据报道，在包括乳腺癌在内的一些实体癌症中升高，我将生成并利用 临床前异种移植模型，以确定减少乳腺癌H3K4me3的策略(目标2)。最后， 致癌PI3K/AKT促进转录能力的其他机制将是 研究，重点是AKT介导的H3T45磷酸化的功能后果(S)(AIM 3)。这些目标的完成将有助于进一步理解 PI3K/AKT信号转导，并将为PI3K激活的乳房和其他疾病的未来治疗方案提供信息 癌症。 我的博士研究调查了病毒编码的癌蛋白激活AKT和AKT的机制 MTORC1促进翻译和致癌生长。目前我是美国癌症学会会员。 Tom Roberts博士的实验室发现了PI3K/AKT介导转录能力的机制。这些 持续不断的机会让我做好了广泛的准备，以实现我的首要职业目标--揭露小说 PI3K去调控导致癌症的机制和利用这一认识来发展 持久有效的癌症治疗方法。我的导师，DFCI癌症生物系，和 更大的DFCI和哈佛医学院社区装备精良，致力于为我提供 必要的资源和基础设施，以实现我的研究计划中概述的目标，并努力实现 实现我长期的职业目标。

PROJECT SUMMARY PI3K/AKT pathway activation, most commonly occurring through PIK3CA mutation or PTEN inactivation, deregulates cell growth, metabolism, and cell survival and is a common and significant event in human cancer. Research now suggests that cancer is both a genetic and epigenetic disease, as changes to the chromatin landscape frequently occur. High levels of the H3K4me3 mark, indicative of transcriptional competence, is associated with a poor prognosis in some cancer types. The H3K4 histone demethylase KDM5A may mediate a drug resistant state in response to EGFR inhibition in PI3K-mutated cancers. Moreover, AKT previously was shown to decrease H3K27me3 through the phosphorylation of the H3K27 methyltransferase EZH2. I therefore investigated whether PI3K/AKT regulates transcriptional competence. My preliminary research and first, first- authored manuscript from my postdoctoral research demonstrate that AKT promotes cell growth by directly regulating KDM5A and increasing H3K4me3. These data provide the foundation for my future research goals described below. My immediate career goals are to ethically conduct high quality science and to publish my research in top tier, peer reviewed journals, such that I can become an independent investigator at the intersection of chromatin biology and oncogenic signaling. My immediate research-oriented goals are 100% embodied by the research plan I propose for the K99/R00. Within this proposal, I plan to first develop of a comprehensive understanding of how oncogenic PI3K/AKT promotes H3K4me3 (Aim 1). Because H3K4me3 has been reported as elevated in some solid cancers including breast cancer, I will generate and utilize preclinical xenograft models to define a strategy to reduce H3K4me3 in breast cancer (Aim 2). Finally, additional mechanisms by which oncogenic PI3K/AKT promotes transcriptional competence will be investigated, focusing on the functional consequence(s) of AKT-mediated H3T45 phosphorylation (Aim 3). Completion of these aims will provide additional understanding of the mechanistic underpinnings of PI3K/AKT signal transduction, and will inform future therapeutic regimens in PI3K-activated breast and other cancers. My doctoral research investigated the mechanisms by which a virally encoded oncoprotein activates AKT and mTORC1 to promote translation and oncogenic growth. Currently I am an American Cancer Society fellow in Dr. Tom Roberts' lab identifying mechanisms by which PI3K/AKT mediate transcriptional competence. These ongoing opportunities have extensively prepared me to address my overarching career goal to expose novel mechanisms by which PI3K deregulation drives cancer and exploit this understanding to develop durable and efficacious therapies for cancer. My mentor, the DFCI Cancer Biology department, and the larger DFCI and Harvard Medical School community are well-equipped and committed to providing me with the necessary resources and infrastructure to address the aims outlined in my research plan and work towards the accomplishment of my long-term career goals.