Downregulation of MYPT1 increases tumor resistance in ovarian cancer by targeting the Hippo pathway and increasing the stemness
Open Access
- 11 January 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Molecular Cancer
- Vol. 19 (1), 1-16
- https://doi.org/10.1186/s12943-020-1130-z
Abstract
Ovarian cancer is one of the most common and malignant cancers, partly due to its late diagnosis and high recurrence. Chemotherapy resistance has been linked to poor prognosis and is believed to be linked to the cancer stem cell (CSC) pool. Therefore, elucidating the molecular mechanisms mediating therapy resistance is essential to finding new targets for therapy-resistant tumors. shRNA depletion of MYPT1 in ovarian cancer cell lines, miRNA overexpression, RT-qPCR analysis, patient tumor samples, cell line- and tumorsphere-derived xenografts, in vitro and in vivo treatments, analysis of data from ovarian tumors in public transcriptomic patient databases and in-house patient cohorts. We show that MYPT1 (PPP1R12A), encoding myosin phosphatase target subunit 1, is downregulated in ovarian tumors, leading to reduced survival and increased tumorigenesis, as well as resistance to platinum-based therapy. Similarly, overexpression of miR-30b targeting MYPT1 results in enhanced CSC-like properties in ovarian tumor cells and is connected to the activation of the Hippo pathway. Inhibition of the Hippo pathway transcriptional co-activator YAP suppresses the resistance to platinum-based therapy induced by either low MYPT1 expression or miR-30b overexpression, both in vitro and in vivo. Our work provides a functional link between the resistance to chemotherapy in ovarian tumors and the increase in the CSC pool that results from the activation of the Hippo pathway target genes upon MYPT1 downregulation. Combination therapy with cisplatin and YAP inhibitors suppresses MYPT1-induced resistance, demonstrating the possibility of using this treatment in patients with low MYPT1 expression, who are likely to be resistant to platinum-based therapy.Keywords
Funding Information
- Ministerio de Ciencia, Innovación y Universidades (RTI2018-097455-B-I00)
- Centro de Investigacion Biomedica en Red-Cancer (CB16/12/00275)
- Consejería de Salud, Junta de Andalucía (PI-0397-2017)
- Instituto de Salud Carlos III (CD16/00230)
- Fundación Científica Asociación Española Contra el Cáncer
- Fundación Eugenio Rodríguez Pascual
This publication has 50 references indexed in Scilit:
- LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic markerNature Medicine, 2012
- The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domainProceedings of the National Academy of Sciences of the United States of America, 2012
- LATS1/WARTS phosphorylates MYPT1 to counteract PLK1 and regulate mammalian mitotic progressionThe Journal of cell biology, 2012
- E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway componentsProceedings of the National Academy of Sciences of the United States of America, 2011
- Integrated genomic analyses of ovarian carcinomaNature, 2011
- Ovarian cancer stem-like side-population cells are tumourigenic and chemoresistantBritish Journal of Cancer, 2010
- The biology of ovarian cancer: new opportunities for translationNature Reviews Cancer, 2009
- Myosin Phosphatase-Targeting Subunit 1 Regulates Mitosis by Antagonizing Polo-like Kinase 1Developmental Cell, 2008
- Structural basis of protein phosphatase 1 regulationNature, 2004
- Three clonal types of keratinocyte with different capacities for multiplication.Proceedings of the National Academy of Sciences of the United States of America, 1987