Epigenetic Silencing of β-Spectrin, a TGF-β Signaling/Scaffolding Protein in a Human Cancer Stem Cell Disorder

Abstract

Hereditary cancer syndromes provide powerful insights into dysfunctional signaling pathways that lead to sporadic cancers. Beckwith-Wiedemann syndrome (BWS) is a hereditary human cancer stem cell syndrome currently linked to deregulated imprinting at chromosome 11p15 and uniparental disomy. However, causal molecular defects and genetic models have remained elusive to date in the majority of cases. The non-pleckstrin homology domain β-spectrin (β2SP) (the official name for human is Spectrin, beta, nonerythrocytic 1 (SPTBN1), isoform 2; the official name for mouse is Spectrin beta 2 (Spnb2), isoform 2), a scaffolding protein, functions as a potent TGF-β signaling member adaptor in tumor suppression and development. Yet, the role of the β2SP in human tumor syndromes remains unclear. Here, we report that β2SP+/− mice are born with many phenotypic characteristics observed in BWS patients, suggesting that β2SP mutant mice phenocopy BWS, and β2SP loss could be one of the mechanisms associated with BWS. Our results also suggest that epigenetic silencing of β2SP is a new potential causal factor in human BWS patients. Furthermore, β2SP+/− mice provide an important animal model for BWS, as well as sporadic cancers associated with it, including lethal gastrointestinal and pancreatic cancer. Thus, these studies could lead to further insight into defects generated by dysfunctional stem cells and identification of new treatment strategies and functional markers for the early detection of these lethal cancers that otherwise cannot be detected at an early stage.

Effect of desipramine on gene expression in the mouse frontal cortex – Microarray study

“…Kinesin's role has been described in studies of the regeneration of damaged nerves, where its mRNA level was increased [33]. Spectrin (Spnb2) regulates signal transduction; the knockout of this gene resulted in anatomical abnormalities as a result of the disturbances in the TGF-b signal transduction pathway in heterozygote mice [34].…”

Targeting cancer stem cells in hepatocellular carcinoma

“…Disruption of TGF-β signaling yields a phenotype similar to that of a human CSC disorder, BeckwithWiedemann syndrome, a disease characterized by stem cell alteration. 38 Loss or reduced expression of the TGF-β receptor (TβRI/TβRII) or signaling molecules (eg, Smad 4) also enhances malignant progression in various human tumor types, cancer xenografts, and transgenic mice. [39][40][41][42][43][44][45] This is at least partially due to the activation of mitogenic and oncogenic pathways involving CDK4, PRAJA, β-catenin, TERT, and c-MYC, that occurs when the TGF-β pathway is inactivated.…”

Transforming growth factor‐β in liver cancer stem cells and regeneration

“…For instance, TBRII is mutated in up to 30% of colon cancers,56 TBRI is mutated in 15% of biliary cancers,57, 58, 59 and SMAD4 is deleted in 40%‐60% of pancreatic cancers and mutated in gastrointestinal cancer 60. Loss of β2SP is observed in human HCC 14, 61, 62, 63. Evidence from Smad4‐knockout mice, which develop head and neck cancers, demonstrates a significant role for Smad4 in promoting genomic stability 64.…”