RESUMO
The lesion bypass pathway, which is regulated by monoubiquitination of proliferating cell nuclear antigen (PCNA), is essential for resolving replication stalling due to DNA lesions. This process is important for preventing genomic instability and cancer development. Previously, it was shown that cells deficient in tumour suppressor p33ING1 (ING1b) are hypersensitive to DNA damaging agents via unknown mechanism. In this study, we demonstrated a novel tumour suppressive function of ING1b in preserving genomic stability upon replication stress through regulating PCNA monoubiquitination. We found that ING1b knockdown cells are more sensitive to UV due to defects in recovering from UV-induced replication blockage, leading to enhanced genomic instability. We revealed that ING1b is required for the E3 ligase Rad18-mediated PCNA monoubiquitination in lesion bypass. Interestingly, ING1b-mediated PCNA monoubiquitination is associated with the regulation of histone H4 acetylation. Results indicate that chromatin remodelling contributes to the stabilization of stalled replication fork and to the regulation of PCNA monoubiquitination during lesion bypass.
Assuntos
Dano ao DNA , Instabilidade Genômica , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Proteínas Nucleares/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Acetilação , Linhagem Celular , Replicação do DNA , Proteínas de Ligação a DNA/metabolismo , Técnicas de Silenciamento de Genes , Histonas/metabolismo , Humanos , Proteína 1 Inibidora do Crescimento , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Fase S , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases , Ubiquitinação , Raios UltravioletaRESUMO
The inhibitor of growth (ING) family of tumor suppressors has five members and is implicated in the control of apoptosis, senescence, DNA repair, and cancer progression. However, little is known about ING activity in the regulation of cancer progression. ING members and splice variants seem to behave differently with respect to cancer invasion and metastasis. Interaction with histone trimethylated at lysine 4 (H3K4me3), hypoxia inducible factor-1 (HIF-1), p53, and nuclear factor kappa-B (NF-kappaB) are potential mechanisms by which ING members exert effects on invasion and metastasis. Subcellular mislocalization, rapid protein degradation, and to a lesser extent ING gene mutation are among the mechanisms responsible for inappropriate ING levels in cancer cells. The aim of this review is to summarize the different roles of ING family tumor suppressors in cancer progression and the molecular mechanisms involved.
Assuntos
Apoptose/fisiologia , Inibidores do Crescimento/fisiologia , Histonas/metabolismo , NF-kappa B/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Apoptose/genética , Reparo do DNA , Crescimento/genética , Inibidores do Crescimento/genética , Histonas/genética , Humanos , Mutação , NF-kappa B/genética , Neoplasias/genética , Processos Neoplásicos , Proteína Supressora de Tumor p53/metabolismoRESUMO
Cadherin-like protein 22 (CDH22) is a transmembrane glycoprotein implicated in cell-cell adhesion and cancer metastasis. The expression of CDH22 has been shown to be increased in colorectal cancers. However, the role of CDH22 in melanomagenesis is not known. To investigate the role of CDH22 in melanoma progression, we examined the expression of CDH22 in melanocytic lesions at different stages and analysed the correlation between CDH22 expression and clinicopathlogic parameters and patient survival. Using tissue microarray and immunohisto-chemistry, we evaluated CDH22 staining in 76 dysplastic nevi, 247 primary melanomas, and 143 metastatic melanomas. We found that metastatic melanomas had a significantly higher percentage of negative CDH22 staining than dysplastic nevi (P = 0.012) and primary melanomas (P = 0.038). CDH22 expression was also reduced in thick (≥2 mm) and ulcerative melanomas (P = 0.003 and 0.022, respectively). Melanomas of AJCC stage II, III, and IV had a higher percentage of negative CDH22 staining than AJCC stage I melanomas (P = 0.004, P < 0.0001, and P = 0.009, respectively). Melanomas with negative CDH22 expression had significantly poorer disease-specific 5-year survival than those with positive CDH22 staining. Additionally, CDH22 expression depended on AJCC stage to predict patient survival. These data indicate that reduced CDH22 expression is associated with melanoma metastasis and poor patient prognosis.