The role of mechano-regulated YAP/TAZ in erectile dysfunction.

Phosphodiesterase type 5 inhibitors (PDE5is) constitute the primary therapeutic option for treating erectile dysfunction (ED). Nevertheless, a substantial proportion of patients, approximately 30%, do not respond to PDE5i treatment. Therefore, new treatment methods are needed. In this study, we identified a pathway that contributes to male erectile function. We show that mechano-regulated YAP/TAZ signaling in smooth muscle cells (SMCs) upregulates adrenomedullin transcription, which relaxed the SMCs to maintain erection. Using single-nucleus RNA sequencing, we investigated how penile erection stretches the SMCs, inducing YAP/TAZ activity. Subsequently, we demonstrate that YAP/TAZ plays a role in erectile function and penile rehabilitation, using genetic lesions and various animal models. This mechanism relies on direct transcriptional regulation of adrenomedullin by YAP/TAZ, which in turn modulates penile smooth muscle contraction. Importantly, conventional PDE5i, which targets NO-cGMP signaling, does not promote erectile function in YAP/TAZ-deficient ED model mice. In contrast, by activating the YAP/TAZ-adrenomedullin cascade, mechanostimulation improves erectile function in PDE5i nonrespondent ED model rats and mice. Furthermore, using clinical retrospective observational data, we found that mechanostimulation significantly promotes erectile function in patients irrespective of PDE5i use. Our studies lay the groundwork for exploring the mechano-YAP/TAZ-adrenomedullin axis as a potential target in the treatment of ED.

VASN promotes proliferation of laryngeal cancer cells via YAP/TAZ.

PURPOSE: To explore whether vasorin protein (VASN) can affect the proliferation of laryngeal cancer cells through the regulation of yes-associated protein (YAP)/TAZ (transcriptional co-activator with PDZ binding motif), and then promote the development of laryngeal cancer. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of VASN in laryngeal carcinoma tissues and different T-stage tumor patients, and the correlation between VASN expression and clinicopathological features was analyzed. The diagnostic value of VASN for laryngeal cancer was assessed by receiver operating characteristic (ROC) analysis. Kaplan-Meier method was used to plot the survival curves of patients with different VASN expression levels. After knocking down VASN in Hep-2 cells or in overexpressing VASN in TU212 cells, cell viability, proliferation ability and protein expression level of YAP/TAZ were detected by cell counting kit-8 (CCK-8), plate cloning assay and Western blot. Furthermore, YAP was overexpressed or knocked down simultaneously to evaluate its effect on the viability and proliferation ability of cells. RESULTS: The expression of VASN in laryngeal carcinoma was significantly higher than that in the normal control group, while, at the same time, the expression of VASN in the t3+t4 tumor patients was significantly higher than that in the t1+t2 tumors. We also found that the expression level of VASN was closely related to N stage, T stage, and lymph node metastasis, suggesting that VASN had a certain diagnostic value for laryngeal cancer. After knocking down VASN in cells, the cell viability, proliferative capacity and YAP/TAZ protein expression level decreased significantly. Besides, overexpressing YAP could reverse the inhibition of cell viability and proliferation ability caused by VASN knockdown. CONCLUSIONS: VASN can promote the development of laryngeal cancer by affecting the expression of YAP/TAZ.