Basu-Roy Upal, Bayin N Sumru, Rattanakorn Kirk, Han Eugenia, Placantonakis Dimitris G, Mansukhani Alka, Basilico Claudio
Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.
Department of Neurosurgery, New York University School of Medicine, New York, New York 10016, USA.
Nat Commun. 2015 Apr 2;6:6411. doi: 10.1038/ncomms7411.
The repressive Hippo pathway has a profound tumour suppressive role in cancer by restraining the growth-promoting function of the transcriptional coactivator, YAP. We previously showed that the stem cell transcription factor Sox2 maintains cancer stem cells (CSCs) in osteosarcomas. We now report that in these tumours, Sox2 antagonizes the Hippo pathway by direct repression of two Hippo activators, Nf2 (Merlin) and WWC1 (Kibra), leading to exaggerated YAP function. Repression of Nf2, WWC1 and high YAP expression marks the CSC fraction of the tumor population, while the more differentiated fraction has high Nf2, high WWC1 and reduced YAP expression. YAP depletion sharply reduces CSCs and tumorigenicity of osteosarcomas. Thus, Sox2 interferes with the tumour-suppressive Hippo pathway to maintain CSCs in osteosarcomas. This Sox2-Hippo axis is conserved in other Sox2-dependent cancers such as glioblastomas. Disruption of YAP transcriptional activity could be a therapeutic strategy for Sox2-dependent tumours.
具有抑制作用的Hippo信号通路通过抑制转录共激活因子YAP的促生长功能，在癌症中发挥着重要的肿瘤抑制作用。我们之前的研究表明，干细胞转录因子Sox2维持骨肉瘤中的癌症干细胞（CSC）。我们现在报告，在这些肿瘤中，Sox2通过直接抑制两种Hippo激活因子Nf2（Merlin）和WWC1（Kibra）来拮抗Hippo信号通路，从而导致YAP功能过度增强。Nf2、WWC1的抑制以及YAP的高表达标志着肿瘤群体中的CSC部分，而分化程度较高的部分则具有高Nf2、高WWC1和降低的YAP表达。YAP的缺失会显著减少骨肉瘤中的CSC和致瘤性。因此，Sox2干扰具有肿瘤抑制作用的Hippo信号通路，以维持骨肉瘤中的CSC。这种Sox2-Hippo轴在其他依赖Sox2的癌症如胶质母细胞瘤中是保守的。破坏YAP的转录活性可能是治疗依赖Sox2的肿瘤的一种策略。
