P190A inactivating mutations cause aberrant RhoA activation and promote malignant transformation via the Hippo-YAP pathway in endometrial cancer

Xiaoli Wen,Shuangdi Li,Kai Wang,Wen Lu,Qizhi He,Binya Liu,Zhen Qian,Mengfei Wang,Kun Gao,Jing Wan,Xiaoping Wan,Mei Jiang

doi:10.1038/s41392-020-0170-6

Abstract

The Rho family of GTPases is strictly regulated by a large family of GTPase-activating proteins (GAPs) that stimulate the relatively weak intrinsic GTP-hydrolyzing activity of Rho GTPases. p190A is a potent and widely expressed GAP that acts on RhoA GTPases. p190A is frequently mutated in endometrial cancer, but the contribution of p190A mutations to endometrial tumorigenesis remains unclear. Here we identified that p190A is an upstream regulator of the Hippo-YAP signaling pathway, which is a critical regulator of cell proliferation, apoptosis, and cell fate. p190A knockout in endometrial cancer cells promoted cell proliferation, migration, and epithelial–mesenchymal transition (EMT), which were partially dependent on YAP activation. Wild-type p190A, but not endometrial cancer-associated mutants, suppressed the nuclear localization, transcriptional activity, and malignant transformation function of YAP. Moreover, the nuclear localization of YAP was enhanced in p190A-mutated endometrial cancer. These findings reveal novel molecular mechanisms underlying Hippo-YAP pathway-driven endometrial tumorigenesis and elucidate the potential for therapy targeting the Hippo-YAP pathway in p190A-mutated endometrial cancer.

Highlights

Endometrial cancer is the sixth most common neoplasm in females worldwide and causes ∼74,000 deaths per year.[1]
The co-occurrence of p190A and POLE mutations was observed in endometrial cancer (Fig. 1e)
We focused on the potential role of p190A in epithelial–mesenchymal transition (EMT), an evolutionarily conserved developmental process that has been implicated in tumorigenesis and confers metastatic features upon cancer cells by enhancing migration, invasion, and apoptotic resistance.[12]

Summary

1234567890();,: INTRODUCTION

Endometrial cancer is the sixth most common neoplasm in females worldwide and causes ∼74,000 deaths per year.[1]. P190A KO leads to aberrant activity of the Hippo-YAP pathway The Hippo-YAP pathway plays a critical role in EMT.[13] We noticed that several p190A-regulated EMT-related genes, such as CTGF, Fig. 1 p190A is frequently mutated and downregulated in the TCGA cohort of endometrial cancer patients. Verteporfin treatment reversed the prooncogenic phenotypes observed in p190A-KO Ishikawa cells (Supplementary Fig. 6e–h) Taken together, these results indicate that p190A KO leads to EMT, at least in part, through activation of Hippo-YAP transcriptional outputs in endometrial cancer cells. YAP nuclear localization was enhanced in p190A-KD Ishikawa xenografts compared with sh control xenografts (Fig. 6e) These results indicate that p190A mutations are associated with YAP activation in endometrial cancer specimens, supporting a possible pathological role of the Hippo-YAP pathway in p190A mutation-induced carcinogenesis

DISCUSSION

Findings

MATERIALS AND METHODS