Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target

• Type of Material: Article
• Authors: Cara E Shields, Emory University; Sindhu Potlapalli, Emory University; Selma M Cuya-Smith, Emory University; Sarah K Chappell, Emory University; Dongdong Chen, Emory University; Daniel Martinez, University of Pennsylvania; Jennifer Pogoriler, University of Pennsylvania; Komal S Rathi, University of Pennsylvania; Shiv A Patel, Emory University; Kristianne M Oristian, Duke University; Corinne M Linardic, Duke University; John M Maris, University of Pennsylvania; Karmella Haynes, Emory University; Robert Schnepp, Emory University
• Language: English
• Date: 2021-03-27
• Publisher: WILEY
• Publication Version: Final Published Version
• Copyright Statement: © 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/1878-0261.12914
• Title of Journal or Parent Work: MOLECULAR ONCOLOGY
• Volume: 15
• Issue: 8
• Start Page: 2156
• End Page: 2171
• Grant/Funding Information: This work was supported in part by NIH Grant K08‐7K08CA194162‐02 (RWS), NIH Grant R35 CA220500 (JMM), the Sarcoma Foundation of America (RWS), CURE Childhood Cancer (RWS), Austen’s Army (RWS), NIH Grant U54‐CA231630 (CML), NIH Grant F31‐CA254301 (KMO), the Aflac Cancer and Blood Disorders Center Trust (RWS and KAH.), and the William Woods, M.D., Aflac Clinical Investigator Chair (RWS).; Additionally, this study was supported in part by the Emory Flow Cytometry Core (EFCC), one of the Emory Integrated Core Facilities (EICF), and is subsidized by the Emory University School of Medicine. Additional support was provided by the National Center for Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
• Keywords: Oncology; Science & Technology; BMI1; SENESCENCE; Hippo; EXPRESSION; METASTASIS; pediatric cancer; POLYCOMB GROUP PROTEINS; MODELS; epigenetics; PAX3-FOXO1; Life Sciences & Biomedicine; HIPPO PATHWAY; rhabdomyosarcoma; STEM-CELLS
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology

Abstract

Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma. There are two main subtypes of RMS, alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma. ARMS typically encompasses fusion-positive rhabdomyosarcoma, which expresses either PAX3-FOXO1 or PAX7-FOXO1 fusion proteins. There are no targeted therapies for ARMS; however, recent studies have begun to illustrate the cooperation between epigenetic proteins and the PAX3-FOXO1 fusion, indicating that epigenetic proteins may serve as targets in ARMS. Here, we investigate the contribution of BMI1, given the established role of this epigenetic regulator in sustaining aggression in cancer. We determined that BMI1 is expressed across ARMS tumors, patient-derived xenografts, and cell lines. We depleted BMI1 using RNAi and inhibitors (PTC-209 and PTC-028) and found that this leads to a decrease in cell growth/increase in apoptosis in vitro, and delays tumor growth in vivo. Our data suggest that BMI1 inhibition activates the Hippo pathway via phosphorylation of LATS1/2 and subsequent reduction in YAP levels and YAP/TAZ target genes. These results identify BMI1 as a potential therapeutic vulnerability in ARMS and warrant further investigation of BMI1 in ARMS and other sarcomas.