Abnormal methylation of the common PARK2 and PACRG promoter is associated with downregulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia

Abstract

The PARK2 gene, previously identified as a mutated target in patients with autosomal recessive juvenile parkinsonism (ARJP), has recently been found to be a candidate tumor suppressor gene in ovarian, breast, lung and hepatocellular carcinoma that maps to the third common fragile site (CFS) FRA6E. PARK2 is linked to a novel described PACRG gene by a bidirectional promoter containing a defined CpG island in its common promoter region. We have studied the role of promoter hypermethylation in the regulation of PARK2 and PACRG expression in different tumor cell lines and primary patient samples. Abnormal methylation of the common promoter of PARK2 and PACRG was observed in 26% of patients with acute lymphoblastic leukemia and 20% of patients with chronic myelogenous leukemia (CML) in lymphoid blast crisis, but not in ovarian, breast, lung, neuroblastoma, astrocytoma or colon cancer cells. Abnormal methylation resulted in downregulation of PARK2 and PACRG gene expression, while demethylation of ALL cells resulted in demethylation of the promoter and upregulation of PARK2 and PACRG expression. By FISH, we demonstrated that a lack of PARK2 and PACRG expression was due to biallelic hypermethylation and not to deletion of either PARK2 or PACRG in ALL. In conclusion, our results demonstrate for the first time that the candidate tumor suppressor genes PARK2 and PACRG are epigenetically regulated in human leukemia, suggesting that abnormal methylation and regulation of PARK2 and PACRG may play a role in the pathogenesis and development of this hematological neoplasm. ' 2005 Wiley-Liss, Inc.

Correlated break at PARK2/FRA6E and loss of AF-6/Afadin protein expression are associated with poor outcome in breast cancer

“…The absence of correlation between FRA6E break and Parkin expression suggests that other mechanisms are responsible for abnormal expression of Parkin. Abnormal methylation may be one of these mechanisms (Agirre et al, 2005). We hypothesized that the consequences of the PARK2 break on the clinical outcome may be due to a subsequent effect on a 6q gene, telomeric of PARK2.…”

“…The 6q26-qter region contains several genes including PARK2, FOP, TTLL2, AF-6/MLLT4, KIF25, THBS2 and TBP, potentially involved in cancer (Prasad et al, 1993;Taki et al, 1996;Whitcomb et al, 2003;Denison et al, 2003a;Guasch et al, 2004;Agirre et al, 2005). Among these genes, AF-6/MLLT4, located telomeric of PARK2, encodes the Afadin protein, which is crucial for epithelial physiology and development (Ikeda et al, 1999;Zhadanov et al, 1999).…”

Tumorigenesis and neurodegeneration: two sides of the same coin?

“…Finally, epigenetic downregulation of parkin by biallelic hypermethylation of the parkin promoter has been associated with cases of acute lymphoblastic leukemia and chronic myeloid leukemia in blast crisis. (63) However, the contribution of other epigenetically modified genes or aneuploidies in these neoplasms is unclear.…”

Parkin regulates paclitaxel sensitivity in breast cancer via a microtubule‐dependent mechanism

“…In addition, reduced expression and inactivation of Parkin are frequently observed in human cancers [8][9][10][11]. It is also reported that Parkin expression can be epigenetically regulated; its expression can be reduced due to abnormal DNA methylation [12]. These studies suggest that Parkin may play a tumour suppressor role.…”