Abstract 1926: Hippo pathway effectors YAP/TAZ integrate tissue mechanics and Wnt signaling to regulate microRNA biogenesis

Abstract

Abstract Although mechanical cues including extracellular matrix (ECM) stiffness are known to regulate cell and tissue behavior, it remains unclear how these mechanical cues integrate with biochemical signals to control these processes. The Hippo pathway and its transcriptional coactivators YAP and TAZ, which have emerged as major regulators of organ size, proliferation and cancer development, are thought to be involved in this integration. In addition to being regulated by the canonical Hippo pathway, YAP/TAZ have been found to mediate responses to both biochemical and mechanical signals including ECM stiffness and Wnt signaling. Moreover, recent studies have shown that microRNAs (miRNAs) are sensitive to mechanical cues and YAP/TAZ may regulate miRNA biogenesis through mechanotransduction. Although misregulation of YAP/TAZ and miRNA expression are frequently observed in multiple cancers, which appears to be associated with the altered mechanics of the tumor microenvironment, the signaling mechanisms controlling these processes remain poorly understood and controversial. Here we examine how YAP/TAZ integrate biochemical and mechanical signals to regulate miRNA biogenesis. We found that Wnt3A and stiff ECM synergistically lead to nuclear accumulation and activation of YAP/TAZ. Surprisingly, ECM stiffness induces miRNA-18a expression while Wnt3A signaling has an opposite effect on miRNA-18a expression depending on the stiffness of the cellular microenvironment. Thus, YAP/TAZ activity may define a mechanism by which cells respond to ECM stiffness and Wnt signaling to control miRNA biogenesis. Citation Format: Siyang Han, Celeste M. Nelson. Hippo pathway effectors YAP/TAZ integrate tissue mechanics and Wnt signaling to regulate microRNA biogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1926.