A New Target for Chromatin Remodeler Defects in Cancer

我的实验室在环境致癌方面开创了新的研究方向 过去的25年里。我们为化学致癌物确定了新的靶点，为“旧”肿瘤确定了新的功能 抑制基因，并阐明了环境暴露的第一个机制 发育可能会重新编程表观基因组，以增加成年后患癌症的风险。这是我的目标 通过解决具有挑战性的问题来继续推进癌症研究领域，而不是 进行渐进式研究，这虽然安全，但对“拨动针”作用不大。我的目标 获得R35杰出调查员奖是为了将我的努力集中在一个令人兴奋的新 发现，这代表了我们看待染色质重构体缺陷的方式的范式转变 癌症。作为我们关于环境致癌物质如何重新编程的研究的意外副产品 表观基因组，我们发现了细胞表观遗传机制的新功能，以及一种新的方式 染色质重塑基因缺陷导致癌症。关于这一点的首要假设 R35的应用就是编码机制以“读、写、擦”著称 染色质上的表观遗传甲基标记起着第二个作用，同样重要，但在此之前 不受欢迎，编码功能“读，写和擦除”甲基标记在 细胞骨架。我们报告了(Park等人细胞2016)，并用更多的初步数据支持， 许多染色质重构体实际上是双功能蛋白质，既参与 染色质的组蛋白代码和微管的微管蛋白代码。这一洞察力为 一种新的范例，其中细胞的甲基化机制提供两种编码功能，一种是在 染色质和细胞骨架上的一个。它为理解细胞如何利用开辟了新的领域 并用两个不同但同样重要的编码功能来调节一台机器。这是 对癌症研究特别重要，因为我们忽视了染色质缺陷的事实 重塑基因可以直接影响细胞骨架，例如，通过有丝分裂纺锤体缺陷。 这会导致基因组不稳定和细胞骨架缺陷，从而改变移动性，促进转移。 本申请中提出的实验旨在为理解打开新的大门 染色质重构体缺陷对癌症的影响，以及对 对由基因缺陷引起的表观遗传学和细胞骨架改变的疗效 编码双功能染色质-细胞骨架重构体。

My laboratory has pioneered new research directions in environmental carcinogenesis for the past 25 years. We identified new targets for chemical carcinogens, new functions for “old” tumor suppressor genes, and elucidated the first mechanism by which environmental exposures during development could reprogram the epigenome to increase cancer risk in adulthood. It is my goal to continue to advance the field of cancer research by tackling challenging questions, rather than performing incremental research, which while safe, does little to “move the needle”. My objective for obtaining this R35 Outstanding Investigator Award is to focus my efforts on an exciting new discovery, which represents a paradigm shift in how we look at chromatin remodeler defects in cancer. As an unexpected off-shoot of our research on how environmental carcinogens reprogram the epigenome, we discovered a new function for the cell’s epigenetic machinery, and a new way for defects in chromatin remodeler genes to drive cancer. The Overarching Hypothesis for this R35 application is that the coding machinery known for “reading, writing and erasing” epigenetic methyl marks on chromatin plays a second, equally important but heretofore unappreciated, coding function “reading, writing and erasing” methyl marks on the cytoskeleton. We reported (Park et al Cell 2016), and support with additional Preliminary Data, that many chromatin remodelers are actually dual-function proteins, participating in both the Histone Code of chromatin, and the Tubulin Code of microtubules. This insight sets the stage for a new paradigm, wherein the cell’s methylation machinery serves two coding functions, one on chromatin and one on the cytoskeleton. It opens new frontiers for understanding how cells utilize and regulate one machinery with two distinct, but equally important coding functions. This is of special importance for cancer research, as we have been blind to the fact that defects in chromatin remodeler genes can directly impact the cytoskeleton, for example, via mitotic spindle defects that drive genomic instability and cytoskeletal defects that alter mobility to promote metastasis. The experiments proposed in this application are designed to open new doors for understanding the impact of chromatin remodeler defects in cancer, and for the development of therapies with efficacy against both the epigenetic and cytoskeletal alterations caused by defects in genes that encode dual-function chromatin-cytoskeleton remodelers.