Ten-eleven translocation (TET) proteins oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). 5fC and 5caC can be excised and ...repaired by the base excision repair (BER) pathway, implicating 5mC oxidation in active DNA demethylation. Genome-wide DNA methylation is erased in the transition from metastable states to the ground state of embryonic stem cells (ESCs) and in migrating primordial germ cells (PGCs), although some resistant regions become demethylated only in gonadal PGCs. Understanding the mechanisms underlying global hypomethylation in naive ESCs and developing PGCs will be useful for realizing cellular pluripotency and totipotency. In this study, we found that PRDM14, the PR domain-containing transcriptional regulator, accelerates the TET-BER cycle, resulting in the promotion of active DNA demethylation in ESCs. Induction of Prdm14 expression transiently elevated 5hmC, followed by the reduction of 5mC at pluripotency-associated genes, germline-specific genes and imprinted loci, but not across the entire genome, which resembles the second wave of DNA demethylation observed in gonadal PGCs. PRDM14 physically interacts with TET1 and TET2 and enhances the recruitment of TET1 and TET2 at target loci. Knockdown of TET1 and TET2 impaired transcriptional regulation and DNA demethylation by PRDM14. The repression of the BER pathway by administration of pharmacological inhibitors of APE1 and PARP1 and the knockdown of thymine DNA glycosylase (TDG) also impaired DNA demethylation by PRDM14. Furthermore, DNA demethylation induced by PRDM14 takes place normally in the presence of aphidicolin, which is an inhibitor of G1/S progression. Together, our analysis provides mechanistic insight into DNA demethylation in naive pluripotent stem cells and developing PGCs.
Extragonadal germ cell tumors in Japan Ebi, Hiromichi; Nakata, Masanobu; Tahara, Makoto ...
Cancer science,
December 2003, Letnik:
94, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Extragonadal germ cell tumors (EGCT) represent only 2–5% of adult germ cell malignancies. Some publications from Asia have reported inferior treatment outcomes compared to data from an international ...study group. To ascertain whether this is generally the case, here we analyze treatment outcomes for 30 Japanese patients with EGCT. The medical records of 30 patients (25 non‐seminomas and 4 pure seminomas) treated from 1992 to 2002 were reviewed retrospectively. All patients with seminoma achieved long survival except one who died of chemotherapy‐related sepsis. Ten and 11 patients with EGCT presented with mediastinal and retroperitoneal primary sites, respectively. The 5‐year overall survival (OS) and progression‐free survival (PFS) for non‐seminoma was 71% and 42%, respectively. The 5‐year OS and PFS was 60% and 44%, respectively, for 10 patients with mediastinal nonseminoma, and 91% and 48%, respectively, for patients with retroperitoneal nonseminoma. Tumor marker values on day 7 were available for 19 patients. Among the 19 patients in whom AFP or β‐HCG were measured on day 7, the values had declined in 12 patients and were transiently elevated in 7 patients compared to pretreatment values. The transient elevations of tumor markers were significantly associated with poor OS (P=0.02) and PFS (P=0.008). The treatment outcome of Japanese patients with EGCT seemed to be comparable to that reported from international studies, suggesting no difference between ethnic groups. Transient tumor marker elevations on day 7 predict poor survival in EGCT patients and may be a useful parameter for identifying patients requiring more aggressive treatment.
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