RESUMO
Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer with poor prognosis. Cancer stem cells (CSCs) are seeds for tumor relapse and metastasis. However, pathways that maintain stemness genes are not fully understood. Here, we report that the enzyme euchromatic histone lysine methyltransferase 1 (EHMT1) is expressed in primary and relapse ARMS tumors. EHMT1 suppression impaired motility and induced differentiation in ARMS cell lines and reduced tumor progression in a mouse xenograft model in vivo. RNA sequencing of EHMT1-depleted cells revealed downregulation of ALDH1A1 that is associated with CSCs. Consistent with this, inhibition of ALDH1A1 expression and activity mimicked EHMT1 depletion phenotypes and reduced tumorsphere formation. Mechanistically, we demonstrate that EHMT1 does not bind to the ALDH1A1 promoter but activates it by stabilizing C/EBPß, a known regulator of ALDH1A1 expression. Our findings identify a role for EHMT1 in maintenance of stemness by regulating ALDH1A1 expression and suggest that targeting ALDH+ cells is a promising strategy in ARMS. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Família Aldeído Desidrogenase 1/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Células-Tronco Neoplásicas/enzimologia , Retinal Desidrogenase/metabolismo , Rabdomiossarcoma Alveolar/enzimologia , Família Aldeído Desidrogenase 1/genética , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/genética , Humanos , Camundongos Nus , Invasividade Neoplásica , Células-Tronco Neoplásicas/patologia , Fenótipo , Retinal Desidrogenase/genética , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Alveolar/patologia , Transdução de Sinais , Carga TumoralRESUMO
Wnt signaling is downregulated in embryonal rhabdomyosarcoma (ERMS) and contributes to the block of differentiation. Epigenetic mechanisms leading to its suppression are unknown and could pave the way toward novel therapeutic modalities. We demonstrate that EHMT2 suppresses canonical Wnt signaling by activating expression of the Wnt antagonist DKK1. Inhibition of EHMT2 expression or activity in human ERMS cell lines reduced DKK1 expression and elevated canonical Wnt signaling resulting in myogenic differentiation in vitro and in mouse xenograft models in vivo. Mechanistically, EHMT2 impacted Sp1 and p300 enrichment at the DKK1 promoter. The reduced tumor growth upon EHMT2 deficiency was reversed by recombinant DKK1 or LGK974, which also inhibits Wnt signaling. Consistently, among 13 drugs targeting chromatin modifiers, EHMT2 inhibitors were highly effective in reducing ERMS cell viability. Our study demonstrates that ERMS cells are vulnerable to EHMT2 inhibitors and suggest that targeting the EHMT2-DKK1-ß-catenin node holds promise for differentiation therapy.
Assuntos
Epigênese Genética , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Rabdomiossarcoma Embrionário/metabolismo , Via de Sinalização Wnt/fisiologia , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Dimetil Sulfóxido/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Predisposição Genética para Doença , Antígenos de Histocompatibilidade/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Camundongos , Camundongos Nus , Puromicina/farmacologia , Pirazinas/farmacologia , Piridinas/farmacologia , Quinazolinas/farmacologia , Interferência de RNA , Rabdomiossarcoma Embrionário/genéticaRESUMO
Angiomyofibroblastoma is a rare benign soft tissue tumor that arises predominantly in the female genital tract. It occurs less commonly in the scrotum, spermatic cord, and the retroperitoneum. Its diagnosis is based on specific histological and immunopathological features. However, the condition has never been previously described in the extremities. We present the first case report of angiomyofibroblastoma presenting as a slow-growing tumor in the foot of a 48-year-old lady.