Dystrophin is a tumor suppressor in human cancers with myogenic programs

Abstract

Many common human mesenchymal tumors, including gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS), and leiomyosarcoma (LMS), feature myogenic differentiation1–3. Here we report that intragenic deletion of the dystrophin-encoding and muscular dystrophy-associated DMD gene is a frequent mechanism by which myogenic tumors progress to high-grade, lethal sarcomas. Dystrophin is expressed in nonneoplastic and benign counterparts for GIST, RMS and LMS, and the DMD deletions inactivate larger dystrophin isoforms, including 427kDa dystrophin, while preserving expression of an essential 71kDa isoform. Dystrophin inhibits myogenic sarcoma cell migration, invasion, anchorage independence, and invadopodia formation, and dystrophin inactivation was found in 96%, 100%, and 62% of metastatic GIST, embryonal RMS, and LMS, respectively. These findings validate dystrophin as a tumor suppressor and likely anti-metastatic factor, suggesting that therapies in development for muscular dystrophies may also have relevance in treatment of cancer.

Neuronal SH-SY5Y cells use the C-dystrophin promoter coupled with exon 78 skipping and display multiple patterns of alternative splicing including two intronic insertion events

“…Moreover, skeletal muscle tissue also has been reported with highest number of differentially expressed alternative exons (Castle et al 2008;Pan et al 2008). Recently, dystrophin has been reported as a tumor suppressor in human cancers with myogenic programs by disclosing disastrous intragenic deletion in the dystrophin gene (Wang et al 2014). In SH-SY5Y cells with neuronal character, no evidence of intragenic deletion was obtained from dystrophin cDNA analysis.…”

Gastrointestinale Stromatumoren (GIST) – Neues zu Pathologie, Chirurgie und medikamentöser Therapie

“…Eine erhöhte Anzahl an Aberration (> 5) korreliert mit einem instabileren Karyotyp und klinisch aggressiverem Verlauf [24]. Zudem konnte kürzlich gezeigt werden, dass ein Großteil mesenchymaler Tumore (i. e. GIST, Leiomyosarkome und Rhabdomyosarkome) und darunter 96 % der untersuchten metastasierten GIST, inaktivierende Mutationen des DMD-Gens auf Chromosom X aufweisen, welches für das muskeldystrophieassoziierte Protein Dystrophin kodiert [25]. Dystrophin fungiert als Tumorsuppressor, der Zellmigration, Invasion, verankerungsunabhängiges Wachstum und die Ausbildung von Invadopodien hemmt [25].…”

Cavin-1 and Caveolin-1 are both required to support cell proliferation, migration and anchorage-independent cell growth in rhabdomyosarcoma

“…11,22 In addition, defects in tumor suppressors (i.e., p53), 23 cell cycle regulatory genes (i.e., N-Myc, Rb1) 21,24 and structural proteins involved in muscular integrity (i.e., dystrophin, alpha-sarcoglycan and dysferlin) have been reported. [25][26][27][28][29][30] Conversely, ARMS is dominated by the presence of specific chromosomal translocations leading to expression of the fused Pax3-Foxo1 and Pax7-Foxo1 factors, that driving in a cell cycle manner the transcription of several genes normally restricted to the embryonal development favor tumor initiation in some muscle precursors. [31][32][33][34][35][36] A number of important cellular processes, such as endocytosis, cholesterol homeostasis and signal transduction, takes place in small invaginations of the plasma membrane known as caveolae, 37 specialized microdomains whose morphogenesis and function depend on the complex network established between two protein families known as Caveolins (Cav-1, Cav-2 and Cav-3) [38][39][40] and Cavins (Cavin-1, -2, -3 and -4).…”