Novel Mechanisms of Nuclear Phosphoinositide Signaling in the Regulation of the YAP/TAZ Pathway in Triple-Negative Breast Cancer

项目摘要：“核磷酸肌醇信号转导的新机制，在调节的 三阴性乳腺癌中的雅普/TAZ通路” 磷脂酰肌醇（PI）是控制人体生理学许多方面的脂质信使。显著 在细胞核中发现了一部分PI（>总PI的40%），然而，核PI的性质和功能 大部分都是未知的。我们发现磷脂酰肌醇4，5-二磷酸（PI 4，5 P2）是一种丰富的磷脂酰肌醇 细胞核中的磷脂酰肌醇-4-磷酸-5-激酶和产生PI 4，5 P2的激酶1型 α（PIPKI β）是调节核PI 4，5 P2信号传导的主要酶。核PI 4，5 P2可以进一步 由核定位PI 3-激酶（PI 3 K）磷酸肌醇多激酶（IPMK）磷酸化以产生PI 种，PI 3，4，5 P3，其与肿瘤发生有关。这表明PIPKI和IPMK是潜在的 癌症治疗的靶点。因此，我们发现PIPKI的消耗或药理学抑制作用与PIPKI的代谢有关。 IPMK通过三阴性乳腺癌（TNBC）细胞中的细胞凋亡导致癌细胞死亡。此外，在TNBC 我们发现PIPKI β和IPMK的缺失显著降低了雅普/TAZ靶基因的表达， 对肿瘤发生有贡献的基因。TNBC是乳腺癌中最具侵袭性的亚型， 癌症，并且由于缺乏对当前化疗的替代方案而与较差的患者存活率相关。作为 因此，迫切需要在TNBC中发现新的靶向治疗剂。雅普/TAZ-PI激酶 （PIPKI β和IPMK）途径是有吸引力的药物靶点，因为1）雅普/TAZ的异常活化经常与细胞凋亡相关。 在乳腺癌中发现，特别是在TNBC中，PIPKI β基因通常在TNBC中扩增，和2）核转录因子， PI 3，4，5 P3通路在TNBC中经常失调。准确理解核PIs介导的雅普/TAZ 这些研究将提供可用于开发针对TNBC的靶向治疗剂的知识。在这 我们将1）阐明雅普/TAZ通路受PIPIIK介导的分子机制 和IPMK通过广泛的生物化学和细胞生物学方法和2）调查的贡献， 和IPMK在培养的TNBC细胞和小鼠模型中的TNBC发病机制中的作用。该项目将提供关键的 PI信号如何调节雅普/TAZ通路的信息，并阐明靶向靶 通过未充分研究的PIPIK激酶和IPMK在癌症中的雅普/TAZ通路。

Project Summary: “Novel Mechanisms of Nuclear Phosphoinositide Signaling in the Regulation of the YAP/TAZ Pathway in Triple-Negative Breast Cancer” Phosphoinositides (PIs) are lipid messengers that control many aspects of human physiology. A significant fraction of PIs (>40% of total PIs) is found in the nucleus, however the nature and functions of the nuclear PIs are largely unknown. We discovered that phosphatidylinositol 4,5-bisphosphate (PI4,5P2) is an abundant PI species in the nucleus and the PI4,5P2-generating kinase phosphatidylinositol-4-phosphate-5-kinase type 1 alpha (PIPKI) is a major enzyme modulating nuclear PI4,5P2 signaling. Nuclear PI4,5P2 can be further phosphorylated by a nuclear-localizing PI3-kinase (PI3K) inositol phosphate multikinase (IPMK) to produce a PI species, PI3,4,5P3, that has been implicated in oncogenesis. This suggests that PIPKI and IPMK are potential targets for cancer therapy. Consistently, we showed that depletion or pharmacological inhibition of PIPKI and IPMK leads to cancer cell death by apoptosis in triple negative breast cancer (TNBC) cells. Moreover, in TNBC cells, we discovered that depletion of PIPKI and IPMK significantly reduces the expression of YAP/TAZ target genes that have established contributions to oncogenesis. TNBC is the most aggressive subtype of breast cancer and associated with poor patient survival due to lack of alternatives to current chemotherapies. As a result, there is an urgent need for discovering novel targeted therapeutics in TNBC. The YAP/TAZ-PI kinases (PIPKI and IPMK) pathways are attractive drug targets because 1) aberrant activation of YAP/TAZ is frequently found in breast cancer particularly in TNBC, PIPKI gene is commonly amplified in TNBC, and 2) the nuclear PI3,4,5P3 pathway is frequently dysregulated in TNBC. Precise understanding of nuclear PIs-mediated YAP/TAZ pathway will provide knowledge which can be utilized for developing targeted therapeutics against TNBC. In this proposal, we will 1) elucidate molecular mechanisms by which the YAP/TAZ pathway is controlled by PIPIK and IPMK via extensive biochemical and cell biological approaches and 2) investigate contributions of PIPIK and IPMK in TNBC pathogenesis in cultured TNBC cells and mouse models. This project will provide pivotal information how the YAP/TAZ pathway is regulated by the PI signaling and illuminate new routes to target the YAP/TAZ pathway in cancer by the understudied kinases of PIPIK and IPMK.