Open AccessEpigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target
Author(s) -
Shields Cara E.,
Potlapalli Sindhu,
CuyaSmith Selma M.,
Chappell Sarah K.,
Chen Dongdong,
Martinez Daniel,
Pogoriler Jennifer,
Rathi Komal S.,
Patel Shiv A.,
Oristian Kristianne M.,
Linardic Corinne M.,
Maris John M.,
Haynes Karmella A.,
Schnepp Robert W.
Publication year - 2021
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12914
Subject(s) - alveolar rhabdomyosarcoma , rhabdomyosarcoma , cancer research , bmi1 , biology , pax3 , epigenetics , regulator , sarcoma , medicine , microbiology and biotechnology , pathology , stem cell , transcription factor , genetics , gene
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.