Regulative loop between β-Catenin and Protein Tyrosine Phosphatase Receptor Type γ (PTPRG) in Chronic Myeloid Leukemia

Chronic Myeloid Leukemia (CML) is a myeloproliferative disease characterized by the presence of BCR-ABL1 tyrosine kinase. PTPRG (Protein Tyrosine Phoshatase Receptor type γ) is a tumor suppressor gene down-regulated by hypermethylation of its promoter region in CML. Previous studies demonstrated that a re-expression of PTPRG protein is correlated with a decreased colony formation and clonogenic capability of CML cells. In addition, its restored expression was observed in patients after TKI therapy. In order to understand the mutual regulation between this phosphatase and BCR-ABL1, we searched for PTPRG putative interactors among proteins that are downstream BCR-ABL1 driven pathways and we focused on β-Catenin (CTNNB1), that resulted at the same time a PTPRG substrate and its transcriptional regulator. We observed that a modulation of expression and function of PTPRG in CML cell lines leads to changes in phosphorylation and activation of BCR-ABL1 and β-Catenin: PTPRG is able to bind and dephosphorylate the onco-protein β-Catenin causing its cytosolic destabilization and consequent degradation in cells with an exogenous or endogenous expression of PTPRG (K562 and LAMA-84 cell lines). Furthermore, we demonstrated that an increased expression of β-Catenin in PTPRG negative CML cell lines is correlated with an over-expression of the DNA (cytosine-5)-methyltransferase 1 (DNMT1) that is responsible of PTPRG promoter hypermethylation and that inhibition after treatment with 5-Azacydine and down-regulation of this gene are correlated with PTPRG re-expression both at mRNA and protein levels. Here we show for the first time a mechanism that involves β-Catenin degradation and the consequent down-regulation of genes regulated by the TCF4/β-Catenin transcription complex. In return, β-Catenin up-regulation is correlated with an over-expression of DNMT1 that contributes to hypermethylation of PTPRG promoter region. We hypothesized that there is a regulative loop between PTPRG and β-Catenin and that an imbalance of the system in favor of one or the other could determine a different proliferation fate of CML cells and their clinical aggressiveness.