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

• Published in: Oncogene 2024-02, Vol.43 (7), p.524-538
• Main Authors: Kalita, Bhargab, Sahu, Subhashni, Bharadwaj, Anushree, Panneerselvam, Lakshmikanthan, Martinez-Cebrian, Gerard, Agarwal, Megha, Mathew, Sam J.
• Format: Article
• Language: English
• Subjects: 13; 13/44; 14; 14/19; 38; 38/39; 45; 45/91; 631/67/1798; 631/67/2332; 631/80/86/820; 64; 64/60; 82; 82/1; 96; 96/109; Animals; Antigens, Differentiation; Apoptosis; Cell Biology; Cell differentiation; Cell Differentiation - genetics; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Co-Repressor Proteins - genetics; Drug therapy; Histone methyltransferase; Histone Methyltransferases; Human Genetics; Humans; Internal Medicine; Medicine; Medicine & Public Health; Metastases; Mice; Oncology; Rhabdomyosarcoma; Rhabdomyosarcoma - pathology; Skeletal muscle; Therapeutic targets; Tumor cells; Tumorigenesis; Tumors; Wnt protein
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-023-02911-3

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.