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The Wnt-pathway corepressor TLE3 interacts with the histone methyltransferase KMT1A to inhibit differentiation in Rhabdomyosarcoma

Oncogene volume 43, pages 524–538 (2024)Cite this article

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Abstract

Rhabdomyosarcoma tumor cells resemble differentiating skeletal muscle cells, which unlike normal muscle cells, fail to undergo terminal differentiation, underlying their proliferative and metastatic properties. We identify the corepressor TLE3 as a key regulator of rhabdomyosarcoma tumorigenesis by inhibiting the Wnt-pathway. Loss of TLE3 function leads to Wnt-pathway activation, reduced proliferation, decreased migration, and enhanced differentiation in rhabdomyosarcoma cells. Muscle-specific TLE3-knockout results in enhanced expression of terminal myogenic differentiation markers during normal mouse development. TLE3-knockout rhabdomyosarcoma cell xenografts result in significantly smaller tumors characterized by reduced proliferation, increased apoptosis and enhanced differentiation. We demonstrate that TLE3 interacts with and recruits the histone methyltransferase KMT1A, leading to repression of target gene activation and inhibition of differentiation in rhabdomyosarcoma. A combination drug therapy regime to promote Wnt-pathway activation by the small molecule BIO and inhibit KMT1A by the drug chaetocin led to significantly reduced tumor volume, decreased proliferation, increased expression of differentiation markers and increased survival in rhabdomyosarcoma tumor-bearing mice. Thus, TLE3, the Wnt-pathway and KMT1A are excellent drug targets which can be exploited for treating rhabdomyosarcoma tumors.

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Fig. 1: TLE3 regulates Wnt signaling and differentiation in rhabdomyosarcoma cells and skeletal muscle development.
Fig. 2: Loss of TLE3 function inhibits cell migration and proliferation in rhabdomyosarcoma cells.
Fig. 3: Loss of TLE3 function leads to reduced tumorigenic potential in rhabdomyosarcoma.
Fig. 4: Loss of TLE3 function enhances the anti-tumorigenic effect of 6-bromoindirubin-3’-oxime (BIO) in rhabdomyosarcoma.
Fig. 5: TLE3 interacts with the histone methyltransferase KMT1A to regulate differentiation in rhabdomyosarcoma.
Fig. 6: Simultaneous activation of the Wnt pathway by BIO and inhibition of KMT1A by chaetocin suppresses rhabdomyosarcoma tumor growth.
Fig. 7: Model showing the role of TLE3 and KMT1A in rhabdomyosarcoma.

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Data availability

The datasets generated and analyzed during this study are available from the corresponding author on reasonable request. RNA-seq data are available through GEO, GSE202614.

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Acknowledgements

This work was supported by funding from the Indian Council of Medical Research (grant number 5/13/35/2020/NCD-III), Wellcome Trust/DBT India Alliance Intermediate Fellowship (IA/I/13/1/500872) and Science and Engineering Research Board grants (grant number EMR/2016/005218 and CRG/2021/006250) awarded to SJM. We also acknowledge funding from the Regional Center for Biotechnology (RCB). BK is funded by a Science and Engineering Research Board National Postdoctoral Fellowship, AB by a senior research fellowship from the University Grants Commission (UGC) previously and by a senior research fellowship from the Indian Council of Medical Research (ICMR) currently, SS by a senior research fellowship from the Department of Biotechnology (DBT), and MA by a senior research fellowship from ICMR. We thank the RCB microscopy facility for imaging help and the small animal facility (SAF) at the NCR Biotech Science Cluster for help with the animal work. We thank Dr. Asoke Mal (Roswell Park Comprehensive Cancer Center, Buffalo, USA) for the 4RE-Luc, and Myogenin-Luc plasmids, Dr. Charles Murtaugh (University of Utah, Salt Lake City, USA) for the Wnt reporter TOPFLASH and FOPFLASH plasmids and Dr. Thomas Jenuwein (Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany) for the pCMV (myc)3 SUV39H1 plasmid. The Tle3floxed/+ was a kind gift from Dr. Claudio Villanueva (University of Utah, USA). The RH4 and RH28 ARMS cell lines are a kind gift from Dr. Peter Houghton (Greehey Children’s Cancer Research Institute, USA). We acknowledge past and present members of the SJM lab for valuable suggestions and inputs. We acknowledge the support of DBT e-Library Consortium (DeLCON) for providing access to e-resources.

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Author notes

  1. Bhargab Kalita

    Present address: Department of Pathology and Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA

  2. Megha Agarwal

    Present address: Department of Pediatrics, School of Medicine, Stanford University, Stanford, CA, USA

  3. These authors contributed equally: Subhashni Sahu, Anushree Bharadwaj.

Authors and Affiliations

  1. Developmental Genetics Laboratory Regional Centre for Biotechnology (RCB) NCR Biotech Science Cluster 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India

    Bhargab Kalita, Subhashni Sahu, Anushree Bharadwaj, Lakshmikanthan Panneerselvam, Megha Agarwal & Sam J. Mathew

  2. Josep Carreras Leukaemia Research Institute, 08916, Badalona, Spain

    Gerard Martinez-Cebrian

  3. Affiliated to Manipal University, Manipal, Karnataka, 576104, India

    Megha Agarwal & Sam J. Mathew

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Contributions

BK, AB, SS and SJM were involved in experimental design, BK, AB, SS, LP and MA carried out the experiments, BK, AB, SS, LP, GM, MA and SJM analysed and interpreted the results, BK and SJM wrote the manuscript with inputs from AB, SS, LP, GM and MA. All authors read and approved the final manuscript.

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Kalita, B., Sahu, S., Bharadwaj, A. et al. The Wnt-pathway corepressor TLE3 interacts with the histone methyltransferase KMT1A to inhibit differentiation in Rhabdomyosarcoma. Oncogene 43, 524–538 (2024). https://doi.org/10.1038/s41388-023-02911-3

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