SNAIL is a key regulator of alveolar rhabdomyosarcoma tumor growth and differentiation through repression of MYF5 and MYOD function

• Published in: Cell death & disease Vol. 9; no. 6; pp. 643 - 20
• Main Authors: Skrzypek, Klaudia, Kusienicka, Anna, Trzyna, Elzbieta, Szewczyk, Barbara, Ulman, Aleksandra, Konieczny, Pawel, Adamus, Tomasz, Badyra, Bogna, Kortylewski, Marcin, Majka, Marcin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29-05-2018; Springer Nature B.V
• Subjects: 13; 13/1; 13/109; 13/89; 14; 38; 38/5; 38/77; 38/90; 42; 42/35; 42/44; 45/15; 45/29; 82/51; 82/80; 96; 96/106; 96/31; 96/63; Alveoli; Animals; Antibodies; Binding Sites; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Children; DNA, Neoplasm - metabolism; Gene Expression Regulation, Neoplastic; Gene Silencing; Histone Deacetylases - metabolism; Humans; Immunology; Life Sciences; Mesenchyme; Mice, Inbred NOD; Mice, SCID; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Muscle Development; Muscles - metabolism; Muscles - pathology; Myoblasts; MyoD protein; MyoD Protein - metabolism; Myogenic Regulatory Factor 5 - metabolism; Phenotype; Rhabdomyosarcoma; Rhabdomyosarcoma, Alveolar - genetics; Rhabdomyosarcoma, Alveolar - pathology; Snail Family Transcription Factors - metabolism; Snail protein; Up-Regulation - genetics; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-0693-8

Rhabdomyosarcoma (RMS) is a mesenchymal tumor of soft tissue in children that originates from a myogenic differentiation defect. Expression of SNAIL transcription factor is elevated in the alveolar subtype of RMS (ARMS), characterized by a low myogenic differentiation status and high aggressiveness. In RMS patients SNAIL level increases with higher stage. Moreover, SNAIL level negatively correlates with MYF5 expression. The differentiation of human ARMS cells diminishes SNAIL level. SNAIL silencing in ARMS cells inhibits proliferation and induces differentiation
in vitro
, and thereby completely abolishes the growth of human ARMS xenotransplants
in vivo
. SNAIL silencing induces myogenic differentiation by upregulation of myogenic factors and muscle-specific microRNAs, such as miR-206. SNAIL binds to the MYF5 promoter suppressing its expression. SNAIL displaces MYOD from E-box sequences (CANNTG) that are associated with genes expressed during differentiation and G/C rich in their central dinucleotides. SNAIL silencing allows the re-expression of MYF5 and canonical MYOD binding, promoting ARMS cell myogenic differentiation. In differentiating ARMS cells SNAIL forms repressive complex with histone deacetylates 1 and 2 (HDAC1/2) and regulates their expression. Accordingly, in human myoblasts SNAIL silencing induces differentiation by upregulation of myogenic factors. Our data clearly point to SNAIL as a key regulator of myogenic differentiation and a new promising target for future ARMS therapies.