Research Papers:

Camptothecin exhibits topoisomerase1-independent KMT1A suppression and myogenic differentiation in alveolar rhabdomyosarcoma cells

David W. Wolff, Min-Hyung Lee, Mathivanan Jothi, Munmun Mal, Fengzhi Li and Asoke K. Mal _

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Oncotarget. 2018; 9:25796-25807. https://doi.org/10.18632/oncotarget.25376

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David W. Wolff1,*, Min-Hyung Lee1,2,*, Mathivanan Jothi1,3, Munmun Mal1, Fengzhi Li4 and Asoke K. Mal1

1Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

2Current address: Division of Biotechnology Review and Research IV, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA

3Current address: Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bengaluru, KA 560029, India

4Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

*These authors have contributed equally to this work

Correspondence to:

Asoke K. Mal, email: [email protected]

Keywords: camptothecin; rhabdomyosarcoma; methyltransferase; myogenesis

Received: February 22, 2018    Accepted: April 24, 2018    Published: May 25, 2018


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.

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