한빛사논문
- 조회385
Oisun Jung 1,2, Min-jeong Baek 1,2,3, Colin Wooldrik 1,2,3, Keith R Johnson 1,2,4, Kurt W Fisher 2,5, Jinchao Lou 6, Tanei J Ricks 7, Tianmu Wen 8, Michael D Best 6, Vincent L Cryns 8, Richard A Anderson 8 & Suyong Choi 1,2,*
1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
2Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
3Interdisciplinary Graduate Program in Biomedical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
4Department of Oral Biology, University of Nebraska Medical Center, Omaha, NE, USA.
5Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
6Department of Chemistry, University of Tennessee, 1420 Circle Drive, Knoxville, TN 37996, USA.
7Department of Chemistry, University of Memphis, 3744 Walker Avenue,Memphis, TN 38152, USA.
8University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison,Madison, WI, USA.
*Corresponding author: correspondence to Suyong Choi
Abstract
The Hippo pathway effectors Yes-associated protein 1 (YAP) and its homolog TAZ are transcriptional coactivators that control gene expression by binding to TEA domain (TEAD) family transcription factors. The YAP/TAZ–TEAD complex is a key regulator of cancer-specific transcriptional programs, which promote tumor progression in diverse types of cancer, including breast cancer. Despite intensive efforts, the YAP/TAZ–TEAD complex in cancer has remained largely undruggable due to an incomplete mechanistic understanding. Here, we report that nuclear phosphoinositides function as cofactors that mediate the binding of YAP/TAZ to TEADs. The enzymatic products of phosphoinositide kinases PIPKIα and IPMK, including phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (P(I3,4,5)P3), bridge the binding of YAP/TAZ to TEAD. Inhibiting these kinases or the association of YAP/TAZ with PI(4,5)P2 and PI(3,4,5)P3 attenuates YAP/TAZ interaction with the TEADs, the expression of YAP/TAZ target genes, and breast cancer cell motility. Although we could not conclusively exclude the possibility that other enzymatic products of IPMK such as inositol phosphates play a role in the mechanism, our results point to a previously unrecognized role of nuclear phosphoinositide signaling in control of YAP/TAZ activity and implicate this pathway as a potential therapeutic target in YAP/TAZ-driven breast cancer.
논문정보
- Research article
- 2024년 02월 (BRIC 등록일 2024-04-04)
- 국외 연구진
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