Promoter methylation‐mediated inactivation of PCDH10 in acute lymphoblastic leukemia contributes to chemotherapy resistance

Abstract

PCDH10 has been implicated as a tumor suppressor, since epigenetic alterations of this gene have been noted in multiple tumor types. However, to date, studies regarding its role in acute and chronic leukemias are lacking. Here, we have investigated the presence of promoter hypermethylation of two CpG islands of the PCDH10 gene by methylation-specific PCR in 215 cases of various subsets of myeloid- and lymphoid-lineage leukemias. We found that PCDH10 promoter hypermethylation was frequent in both B-cell (81.9%) and T-cell (80%) acute lymphoblastic leukemia (ALL), while it was present in low frequency in most subtypes of myeloid leukemias (25.9%) and rare in chronic myeloid leukemia (2.2%). PCDH10 expression was downregulated via promoter hypermethylation in primary ALL samples (N = 4) and leukemia cell lines (N = 11). The transcriptional repression caused by PCDH10 methylation could be restored by pharmacologic inhibition of DNA methyltransferases. ALL cell lines harboring methylation-mediated inactivation of PCDH10 were less sensitive to commonly used leukemia-specific drugs suggesting that PCDH10 methylation might serve as a biomarker of chemotherapy response. Our results demonstrate that PCDH10 is a target of epigenetic silencing in ALL, a phenomenon that may impact lymphoid-lineage leukemogenesis, serve as an indicator of drug resistance and may also have potential implications for targeted epigenetic therapy.

The Clinical Significance of PCDH10 Promoter Methylation in Patients with Bladder Transitional Cell Carcinoma

“…Promoter methylation may be used as detection, surveillance and prognostication biomarker in tumors, especially when the methylation inactivates tumor suppressor genes [23]. Recently, promoter methylation of PCDH10 in human cancers has been reported [11,12,13,14,15], but the clinical significance of PCDH10 methylation in bladder cancer remains unclear.…”

“…A number of protocadherin genes have been demonstrated as tumor suppressor genes, including PCDH10 [11,12,13,14,15]. PCDH10 protein contains six extracellular cadherin repeats, a transmembrane domain and a cytoplasmic domain.…”

“…PCDH10, also known as protocadherin 10, is a novel member of the cadherin family which functions as a tumor suppressor in multiple -human cancer types [11,12,13,14,15]. Recently, it has been demonstrated that PCDH10 is frequently inactivated due to promoter methylation in tumors and could serve as a tumor-specific biomarker [11,12,13,14,15]. However, the methylation status of PCDH10 and its clinical significance in bladder TCC remains unclear.…”

PCDH10, a novel p53 transcriptional target in regulating cell migration

“…The re-expression of PCDH10 could induce cell cycle arrest, apoptosis, and inhibit cell clonogenicity, though with underlying working mechanism undiscovered; however these proposed functions substantiate the tumor suppressive role of PCDH10. 19,20,28,29 The basic transcriptional regulatory mechanism of PCDH10 gene is absent from the previous studies except for the profound epigenetic studies from tumor samples.…”

“…PCDH10 inactivation through genetic deletion or promoter methylation has been presented in multi-kind of human cancers including colon cancer, gastric cancer, prostate cancer and lymphoid malignancies etc. [10][11][12][18][19][20]30 Moreover, that the methylation level of PCDH10 correlates with clinical parameters manifests the significance of PCDH10 in the tumor progression process. 29 For example, methylation status of PCDH10 is associated with poor prognosis in patients with bladder cancer.…”