KDM5B Is Essential for the Hyperactivation of PI3K/AKT Signaling in Prostate Tumorigenesis

KDM5B (lysine[K]-specific demethylase 5B) is frequently upregulated in various human cancers including prostate cancer. KDM5B controls H3K4me3/2 levels and regulates gene transcription and cell differentiation, yet the contributions of KDM5B to prostate cancer tumorigenesis remain unknown. In this study, we investigated the functional role of KDM5B in epigenetic dysregulation and prostate cancer progression in cultured cells and in mouse models of prostate epithelium–specific mutant Pten/Kdm5b. Kdm5b deficiency resulted in a significant delay in the onset of prostate cancer in Pten-null mice, whereas Kdm5b loss alone caused no morphologic abnormalities in mouse prostates. At 6 months of age, the prostate weight of Pten/Kdm5b mice was reduced by up to 70% compared with that of Pten mice. Pathologic analysis revealed Pten/Kdm5b mice displayed mild morphologic changes with hyperplasia in prostates, whereas age-matched Pten littermates developed high-grade prostatic intraepithelial neoplasia and prostate cancer. Mechanistically, KDM5B governed PI3K/AKT signaling in prostate cancer in vitro and in vivo. KDM5B directly bound the PIK3CA promoter, and KDM5B knockout resulted in a significant reduction of P110α and PIP3 levels and subsequent decrease in proliferation of human prostate cancer cells. Conversely, KDM5B overexpression resulted in increased PI3K/AKT signaling. Loss of Kdm5b abrogated the hyperactivation of AKT signaling by decreasing P110α/P85 levels in Pten/Kdm5b mice. Taken together, our findings reveal that KDM5B acts as a key regulator of PI3K/AKT signaling; they also support the concept that targeting KDM5B is a novel and effective therapeutic strategy against prostate cancer

Bone Marrow Transplantation Restores Follicular Maturation and Steroid Hormones Production in a Mouse Model for Primary Ovarian Failure

Recent studies suggest that bone marrow stem cells (BMSCs) are promising grafts to treat a variety of diseases, including reproductive dysfunction. Primary ovarian failure is characterized by amenorrhea and infertility in a normal karyotype female, with an elevated serum level of follicle-stimulating hormone (FSH) and a decrease level of estrogen caused by a mutation in FSH receptor (FSHR) gene. Currently, there is no effective treatment for this condition. The phenotype of FSHR (−/−) mouse, FORKO (follitropin receptor knockout), is a suitable model to study ovarian failure in humans. Female FORKO mice have elevated FSH, decreased estrogen levels, are sterile because of the absence of folliculogenesis, and display thin uteri and small nonfunctional ovaries. In this study, we determined the effects of BMSC transplantation on reproductive physiology in this animal model. Twenty four hours post BMSC transplantation, treated animals showed detectable estroidogeneic changes in daily vaginal smear. Significant increase in total body weight and reproductive organs was observed in treated animals. Hemotoxylin and eosin (H&E) evaluation of the ovaries demonstrated significant increase in both the maturation and the total number of the follicles in treated animals. The FSH dropped to 40–50% and estrogen increased 4–5.5 times in the serum of treated animals compared to controls. The FSHR mRNA was detected in the ovaries of treated animals. Our results show that intravenously injected BMSCs were able to reach the ovaries of FORKO mice, differentiate and express FHSR gene, make FSHR responsive to FSH, resume estrogen hormone production, and restore folliculogenesis

Amplified DNA from different tissues of animals transplanted by (+/+) or (−/−) donors.

<p>Amplified DNA from different tissues of animals transplanted by (+/+) or (−/−) donors.</p

Changes of total body weight(A), ovaries(B), uterus(C), vagina and cervix(D), and serum level of FSH(E) and estrogen(F) in treated (Tr) Vs control (Ct) animals at different time points of experiment.

<p>For B, C and D organs weight considered as % of total body weight. Both treated and control group had increase in total body weight but BMT group showed significantly more increase than control group (A, P<0.03). As indicated, reproductive organs which are highly modulated by estrogen, showed remarkable increase in weight at all time points of the experiment except for the first week (for B, C, and D, a P value of less than 0.04 obtained). Bone marrow transplanted animals compare to untreated controls showed 40–50% decrease in serum FSH level (E, P<0.03) and 4–5.5 folds increase in serum estrogen (F, P<0.004) at all time points of experiment.</p

Development of the ovary in BMT animal (A) compared to untreated control animal (B).

<p>Both the total number of follicles and the number of antral follicles are significantly higher in BMT compare to control group. Histological evaluation showed on average 28±4 follicles/ovary in treated group with 8±2 follicles at the antral stage compared to only 6±2 with no follicles at antral stage in untreated control mice. Photos have been taken at the same magnification.</p