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

项目总结：《核磷脂酰肌醇信号转导调控的新机制》 YAP/TAZ通路在三阴性乳腺癌中的作用 磷脂酰肌醇(PI)是一种脂类信使，控制着人体生理的许多方面。一个重要的 在细胞核中发现了部分PI(占总PI的40%)，但核PI的性质和功能 在很大程度上是未知的。我们发现磷脂酰肌醇4，5-二磷酸(PI4，5P2)是一种丰富的磷脂 细胞核中的物种与磷脂酰肌醇-4-磷酸-5-激酶1型 α(PIPKI)是调节核PI4、5P2信号转导的主要酶。核PI4，5P2可以进一步 由核定位PI3K(PI3K)磷酸肌醇多激酶(IPMK)磷酸化产生PI 与肿瘤发生有关的物种，PI3，4，5P3。这表明PIPKI和IPMK是很有潜力的 癌症治疗的靶点。我们一致地表明，PIPKI和PIPKI的耗竭或药理抑制 IPMK通过诱导三阴性乳腺癌(TNBC)细胞的凋亡而导致癌细胞死亡。此外，在TNBC中 细胞中，我们发现PIPKI和IPMK的缺失显著降低了YAP/TAZ靶标的表达 已确定对肿瘤发生有贡献的基因。TNBC是乳房中最具侵袭性的亚型 癌症与患者存活率低有关，因为目前的化疗缺乏替代方案。作为一名 结果：临床迫切需要寻找新的靶向治疗方法。YAP/TAZ-PI激酶 (PIPKI、和IPMK)通路是很有吸引力的药物靶点，因为1)YAP/TAZ的异常激活经常发生 PIPKI基因在乳腺癌中发现，特别是在TNBC中，通常在TNBC中扩增，2)核 在TNBC中，PI3、4、5P3信号转导通路经常发生异常。对核PI介导的YAP/TAZ的精确理解 途径将提供可用于开发针对TNBC的靶向治疗的知识。在这 我们将1)阐明PIPIK控制YAP/TAZ途径的分子机制 和IPMK通过广泛的生化和细胞生物学方法，以及2)研究PIPIK的贡献 在培养的TNBC细胞和小鼠模型中，IPMK参与了TNBC的发病。该项目将提供关键的 YAP/TAZ通路如何受PI信号调节的信息，并阐明了靶向 YAP/TAZ通路在肿瘤中的作用--PIPIK、和IPMK等未被充分研究的信号转导通路

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.