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25年。我们确定了化学致癌物的新目标，“老”肿瘤的新功能 抑制基因，并阐明了第一个机制，环境暴露期间 发育可能会重新编程表观基因组，以增加成年期的癌症风险。这是我的目标 通过解决具有挑战性的问题，继续推进癌症研究领域，而不是 进行渐进式研究，虽然安全，但几乎没有“移动针头”。我的目标 获得这个R35杰出研究者奖是把我的努力集中在一个令人兴奋的新的 这一发现代表了我们如何看待染色质重塑缺陷的范式转变， 癌作为我们研究环境致癌物如何重新编程的一个意想不到的分支 我们发现了细胞表观遗传机制的新功能， 染色质重塑基因的缺陷导致癌症。对此的过度假设 R35应用是以"阅读、写、擦"著称的编码机械 染色质上的表观遗传甲基标记起着第二个作用，同样重要，但迄今为止 不受重视，编码功能"阅读，写和擦除"甲基标记上的 细胞骨架我们报告（Park et al Cell 2016），并得到其他初步数据的支持， 许多染色质重塑蛋白实际上是双功能蛋白质，参与细胞的两种功能。 染色质的组蛋白密码和微管的微管蛋白密码。这一见解为以下方面奠定了基础： 一种新的范式，其中细胞的甲基化机制提供两种编码功能，一种是 一个在染色质上，一个在细胞骨架上。它为理解细胞如何利用 用两种不同但同样重要的编码功能来调节一种机制。这一点 这对癌症研究特别重要，因为我们对染色质缺陷的事实视而不见， 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 导致基因组不稳定性和细胞骨架缺陷，从而改变迁移率，促进转移。 本申请中提出的实验旨在为理解打开新的大门 染色质重塑缺陷在癌症中的影响，以及 对由基因缺陷引起的表观遗传和细胞骨架改变的功效， 编码双功能染色质-细胞骨架重塑物。

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.