Special AT-rich sequence binding protein-2 (SATB2) is a nuclear matrix protein that binds to nuclear attachment regions and is involved in chromatin remodeling and transcription regulation. In stem cells, it regulates the expression of genes required for maintaining pluripotency and self-renewal and epithelial-mesenchymal transition (EMT). In this study, we examined the oncogenic role of SATB2 in prostate cancer, and assess whether overexpression of SATB2 in human normal prostate epithelial cells (PrECs) induces properties of cancer stem cells (CSCs). The results demonstrate that SATB2 is highly expressed in prostate cancer cell lines and CSCs, but not in PrECs. Overexpression of SATB2 in PrECs induces cellular transformation which was evident by the formation of colonies in soft agar and spheroids in suspension. Overexpression of SATB2 in PrECs also resulted in induction of stem cell markers (CD44 and CD133), pluripotency maintaining transcription factors (cMyc, Oct4, Sox2, KLF4, and Nanog), cadherin switch and EMT-related transcription factors. Chromatin immunoprecipitation assay demonstrated that SATB2 can directly bind to promoters of Bcl-2, Bsp, Nanog, XIAP, KLF4 and HOXA2, suggesting SATB2 is capable of directly regulating pluripotency/self-renewal, cell survival and proliferation. Since prostate CSCs play a crucial role in cancer initiation, progression, and metastasis, we also examined the effects of SATB2 knockdown on stemness. SATB2 knockdown in prostate CSCs inhibited spheroid formation, cell viability, colony formation, cell motility, migration, and invasion compared to their scrambled control groups. SATB2 knockdown in CSCs also upregulated the expression of E-Cadherin and inhibited the expression of N-Cadherin, Snail, Slug, and Zeb1. The expression of SATB2 was significantly higher in prostate adenocarcinoma compared to normal tissues. Overall, our data suggest that SATB2 acts as an oncogenic factor where it is capable of inducing malignant changes in PrECs by inducing CSC characteristics.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, characterized by persistence hyperglycemia resulting from diminished response to insulin secretion or resistance. The present study evaluated the ameliorative effects of Withaferin-A on T2DM-induced reproductive dysfunction in mice. For the same, mice were intraperitoneally injected with Streptozotocin (STZ), (40 mg/kg/day) for 5 consecutive days to induce T2DM. Mice were then treated with WA (8 mg/kg/day) both in normal and diabetic conditions (STZ+WA). Next, blood glucose levels, OGTT, IPTT, oxidative stress and reproductive parameters were estimated. For reproductive performance, immunofluorescent localization of GnRH-I and ERα in POA and PVN region of hypothalamus and ERα in testes was performed. STZ-induced diabetes triggered reproductive dysfunctions as mediated by low ir-GnRH-I and ERα in the brain and ERα in the testes along with declined testosterone and estradiol levels. Interestingly, treatment with WA significantly reduced the blood glucose levels and enhanced glucose clearance including oxidative stress in the brain, pancreas and testes as indicated by low levels of H2O2 and MDA in STZ+WA. This study report for the first time that WA can efficiently combat T2DM induced reproductive dysfunction via enhancing endogenous testosterone, estrogen and increased ir-GnRH-I and ERα in the brain and ERα in the testes of T2DM mice.