Abstract
Alveolar rhabdomyosarcoma (aRMS) is an aggressive subtype of the most common soft tissue cancer in children. A hallmark of aRMS tumors is incomplete myogenic differentiation despite expression of master myogenic regulators such as MyoD. We previously reported that histone methyltransferase KMT1A suppresses MyoD function to maintain an undifferentiated state in aRMS cells, and that loss of KMT1A is sufficient to induce differentiation and suppress malignant phenotypes in these cells. Here, we develop a chemical compound screening approach using MyoD-responsive luciferase reporter myoblast cells to identify compounds that alleviate suppression of MyoD-mediated differentiation by KMT1A. A screen of pharmacological compounds yielded the topoisomerase I (TOP1) poison camptothecin (CPT) as the strongest hit in our assay system. Furthermore, treatment of aRMS cells with clinically relevant CPT derivative irinotecan restores MyoD function, and myogenic differentiation in vitro and in a xenograft model. This differentiated phenotype was associated with downregulation of the KMT1A protein. Remarkably, loss of KMT1A in CPT-treated cells occurs independently of its well-known anti-TOP1 mechanism. We further demonstrate that CPT can directly inhibit KMT1A activity in vitro. Collectively, these findings uncover a novel function of CPT that downregulates KMT1A independently of CPT-mediated TOP1 inhibition and permits differentiation of aRMS cells.
Highlights
Rhabdomyosarcoma (RMS) is the most common soft tissue cancer in children and adolescents [1]
We previously reported that histone methyltransferase KMT1A suppresses MyoD function to maintain an undifferentiated state in Alveolar rhabdomyosarcoma (aRMS) cells, and that loss of KMT1A is sufficient to induce differentiation and suppress malignant phenotypes in these cells
The results show that CPT-11 treatment results in differentiation of aRMS in an in vivo xenograft model
Summary
Rhabdomyosarcoma (RMS) is the most common soft tissue cancer in children and adolescents [1]. Pediatric RMS has two primary subtypes: embryonal (eRMS) and alveolar (aRMS). Both are diagnosed based on expression of skeletal muscle markers, eRMS and aRMS have differing gene expression, genetics, and patient outcomes [2, 3]. 60% of aRMS tumors harbor the PAX3-FOXO1 fusion oncoprotein resulting from a recurrent t(2;13) chromosome translocation [4, 5]. Approximately 60% of pediatric RMS patients achieve long term survival with current multimodal treatments, more than 70% of those diagnosed with fusion-positive aRMS tumors succumb to their disease [6]. There is an immediate need to improve upon www.oncotarget.com the current standard of care and provide better treatment outcomes for patients with PAX3-FOXO1-positive disease using novel therapeutic approaches [2]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
