Oka S, Leon J, Tsuchimoto D, Sakumi K, Nakabeppu Y
1] Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan [2] Research Center for Nucleotide Pool, Kyushu University, Fukuoka, Japan.
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Oncogenesis. 2014 Oct 13;3(10):e121. doi: 10.1038/oncsis.2014.35.
p53-regulated caspase-independent cell death has been implicated in suppression of tumorigenesis, however, the regulating mechanisms are poorly understood. We previously reported that 8-oxoguanine (8-oxoG) accumulation in nuclear DNA (nDNA) and mitochondrial DNA triggers two distinct caspase-independent cell death through buildup of single-strand DNA breaks by MutY homolog (MUTYH), an adenine DNA glycosylase. One pathway depends on poly-ADP-ribose polymerase (PARP) and the other depends on calpains. Deficiency of MUTYH causes MUTYH-associated familial adenomatous polyposis. MUTYH thereby suppresses tumorigenesis not only by avoiding mutagenesis, but also by inducing cell death. Here, we identified the functional p53-binding site in the human MUTYH gene and demonstrated that MUTYH is transcriptionally regulated by p53, especially in the p53/DNA mismatch repair enzyme, MLH1-proficient colorectal cancer-derived HCT116+Chr3 cells. MUTYH-small interfering RNA, an inhibitor for p53 or PARP suppressed cell death without an additive effect, thus revealing that MUTYH is a potential mediator of p53 tumor suppression, which is known to be upregulated by MLH1. Moreover, we found that the p53-proficient, mismatch repair protein, MLH1-proficient colorectal cancer cell line express substantial levels of MUTYH in nuclei but not in mitochondria, suggesting that 8-oxoG accumulation in nDNA triggers MLH1/PARP-dependent cell death. These results provide new insights on the molecular mechanism of tumorigenesis and potential new strategies for cancer therapies.
p53调控的非半胱天冬酶依赖性细胞死亡与肿瘤发生的抑制有关，然而，其调控机制尚不清楚。我们之前报道过，核DNA（nDNA）和线粒体DNA中8-氧代鸟嘌呤（8-oxoG）的积累通过腺嘌呤DNA糖基化酶MutY同源物（MUTYH）导致单链DNA断裂的积累，从而引发两种不同的非半胱天冬酶依赖性细胞死亡。一条途径依赖于聚ADP核糖聚合酶（PARP），另一条途径依赖于钙蛋白酶。MUTYH缺陷会导致MUTYH相关的家族性腺瘤性息肉病。因此，MUTYH不仅通过避免诱变，还通过诱导细胞死亡来抑制肿瘤发生。在这里，我们确定了人类MUTYH基因中的功能性p53结合位点，并证明MUTYH受p53转录调控，特别是在p53/DNA错配修复酶MLH1功能正常的结直肠癌衍生的HCT116+Chr3细胞中。MUTYH小干扰RNA、p53或PARP抑制剂可抑制细胞死亡，且无叠加效应，从而揭示MUTYH是p53肿瘤抑制的潜在介质，已知其受MLH1上调。此外，我们发现p53功能正常、错配修复蛋白MLH1功能正常的结直肠癌细胞系在细胞核中表达大量MUTYH，但线粒体中不表达，这表明nDNA中8-oxoG的积累会触发MLH1/PARP依赖性细胞死亡。这些结果为肿瘤发生的分子机制提供了新的见解，并为癌症治疗提供了潜在的新策略。
