Ouyang Hanyue, Luong Phi, Frödin Morten, Hansen Steen H
GI Cell Biology Laboratory, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Biotech Research & Innovation Centre (BRIC), University of Copenhagen, 2200, Copenhagen N, Denmark.
Oncogene. 2020 Aug;39(33):5570-5587. doi: 10.1038/s41388-020-1385-2. Epub 2020 Jul 8.
The ARHGAP35 gene encoding p190A RhoGAP (p190A) is significantly altered by both mutation and allelic deletion in human cancer, but the functional implications of such alterations are not known. Here, we demonstrate for the first time that p190A is a tumor suppressor using a xenograft mouse model with carcinoma cells harboring defined ARHGAP35 alterations. In vitro, restoration of p190A expression in carcinoma cells promotes contact inhibition of proliferation (CIP) through activation of LATS kinases and phosphorylation of the proto-oncogenic transcriptional co-activator YAP. In contrast, p190A forms harboring recurrent cancer mutations exhibit loss of function in modulating the Hippo pathway, inducing CIP, as well as attenuated suppression of tumor growth in mice. We determine that p190A promotes mesenchymal to epithelial transition (MET) and elicits expression of a cassette of epithelial adherens junction-associated genes in a cell density-dependent manner. This cassette includes CDH1 encoding E-cadherin, which amplifies p190A-mediated LATS activation and is necessary for CIP. Oppositely, we establish that p190A is obligatory for E-cadherin to activate LATS kinases and induce CIP. Collectively, this work defines a novel mechanism by which p190A and E-cadherin cooperate in modulating Hippo signaling to suppress tumor cell growth.
编码p190A RhoGAP（p190A）的ARHGAP35基因在人类癌症中因突变和等位基因缺失而发生显著改变，但其改变的功能影响尚不清楚。在此，我们首次使用携带特定ARHGAP35改变的癌细胞异种移植小鼠模型证明p190A是一种肿瘤抑制因子。在体外，癌细胞中p190A表达的恢复通过激活LATS激酶和原癌基因转录共激活因子YAP的磷酸化来促进增殖接触抑制（CIP）。相反，携带复发性癌症突变的p190A形式在调节Hippo通路、诱导CIP以及减弱小鼠肿瘤生长抑制方面表现出功能丧失。我们确定p190A以细胞密度依赖性方式促进间充质向上皮转化（MET）并引发一组上皮黏附连接相关基因的表达。该基因盒包括编码E-钙黏蛋白的CDH1，它放大了p190A介导的LATS激活，并且是CIP所必需的。相反，我们证实E-钙黏蛋白激活LATS激酶并诱导CIP需要p190A。总的来说，这项工作定义了一种新机制，通过该机制p190A和E-钙黏蛋白协同调节Hippo信号以抑制肿瘤细胞生长。
