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Gliomas are the most common and devastating central nervous system neoplasms. A gender bias exists in their development: females are at lower risk than males, implicating estrogen-mediated protective effects. Estrogen functions are mediated by two ER subtypes: ERα, that functions as tumor promoter and ERβ that function as tumor suppressor. We examined the potential use of ERβ agonists as a novel therapeutic to curb the growth of gliomas. Western analysis of six glioma model cells showed detectable expression of ERβ with little or no ERα. Treatment of glioma cells with ERβ agonists resulted in significant decrease in proliferation. IHC analysis of tumor tissues revealed that ERβ expression is down regulated in high-grade gliomas. We found that ERβ agonists promote both expression and tumor suppressive functions of ERβ in glioma cells. Liquiritigenin, a plant-derived ERβ agonist significantly reduced in vivo tumor growth in a xenograft model. Compared to control mice, animals treated with liquiritigenin had greater than 50% reduction in tumor volume and size. IHC analysis of tumors revealed a significant increase in the nuclear ERβ expression with a concomitant decrease in cell proliferation in the liquiritigenin-treated group. Our results suggest that ERβ signaling has a tumor suppressive function in gliomas. Since ERβ agonists are currently in clinical trials and are well tolerated with fewer side effects, identification of an ERβ agonist as a therapeutic agent can be readily extended to clinical use with current chemotherapies, providing an additional tool for enhancing survival in glioma patients.

Background: Translesion synthesis involves proliferating cell nuclear antigen (PCNA) monoubiquitination and polymerase switching. Results: C1orf124 is required for cell survival following UV damage. It binds to monoubiquitinated PCNA and participates in polymerase switching. Conclusion: C1orf124 serves as a central platform that facilitates translesion synthesis. Significance: This study provides a mechanism for translesion synthesis.

Histone methylation has a key role in oestrogen receptor (ERa)-mediated transactivation of genes. Proline glutamic acid and leucine-rich protein 1 (PELP1) is a new proto-oncogene that functions as an ERa co-regulator. In this study, we identified histone lysine demethylase, KDM1, as a new PELP1-interacting protein. These proteins, PELP1 and KDM1, were both recruited to ERa target genes, and PELP1 depletion affected the dimethyl histone modifications at ERa target genes. Dimethyl-modified histones H3K4 and H3K9 are recognized by PELP1, and PELP1 alters the substrate specificity of KDM1 from H3K4 to H3K9. Effective demethylation of dimethyl H3K9 by KDM1 requires a KDM1-ERa-PELP1 functional complex. These results suggest that PELP1 is a reader of H3 methylation marks and has a crucial role in modulating the histone code at the ERa target genes.