Prognostic and therapeutic value of the Hippo pathway, RABL6A, and p53-MDM2 axes in sarcomas

Abstract

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Chandni Desai1^,2^,*, Jon Thomason1^,*, Jordan L. Kohlmeyer3^,4, Anna C. Reisetter5, Parmanand Ahirwar6, Khadijeh Jahanseir7, Mariah Leidinger1, Georgina Ofori-Amanfo1, Karen Fritchie7, Sadanandan E. Velu6, Patrick Breheny5, Dawn E. Quelle3^,4^,8 and Munir R. Tanas1^,4^,8 1 Department of Pathology, University of Iowa, Iowa City, IA, USA 2 Carver College of Medicine, University of Iowa, Iowa City, IA, USA 3 Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA, USA 4 Molecular Medicine Graduate Program, University of Iowa, Iowa City, IA, USA 5 Department of Biostatistics, University of Iowa, Iowa City, IA, USA 6 Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL, USA 7 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA 8 Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA * These authors contributed equally to this work Correspondence to: Munir R. Tanas, email: munir-tanas@uiowa.edu Keywords: sarcoma; YAP; TAZ; p53-MDM2; RABL6A Received: February 12, 2021 Accepted: March 15, 2021 Published: PUBLISHED_DATE Copyright: © 2021 Desai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Additional prognostic and therapeutic biomarkers effective across different histological types of sarcoma are needed. Herein we evaluate expression of TAZ and YAP, the p53-MDM2 axis, and RABL6A, a novel oncoprotein with potential ties to both pathways, in sarcomas of different histological types. Immunohistochemical staining of a tissue microarray including 163 sarcomas and correlation with clinical data showed that elevated YAP and TAZ independently predict worse overall and progression-free survival, respectively. In the absence of p53 expression, combined TAZ and YAP expression adversely affect overall, progression free, and metastasis free survival more than TAZ or YAP activation alone. RABL6A independently predicted shorter time to metastasis and was positively correlated with p53, MDM2 and YAP expression, supporting a possible functional relationship between the biomarkers. Network analysis further showed that TAZ is positively correlated with MDM2 expression. The data implicate all five proteins as clinically relevant downstream players in the Hippo pathway. Finally, a novel inhibitor of MDM2 (MA242), effectively suppressed the survival of sarcoma cell lines from different histological types regardless of p53 status. These findings suggest both independent and cooperative roles for all five biomarkers across different histological types of sarcoma in predicting patient outcomes and potentially guiding future therapeutic approaches.