SP1 regulates BMSC osteogenic differentiation through the miR-133a-3p/MAPK3 axis : SP1 regulates osteogenic differentiation of BMSCs.

BACKGROUND: The progression of osteoporosis (OP) can dramatically increase the risk of fractures, which seriously disturb the life of elderly individuals. Specific protein 1 (SP1) is involved in OP progression. However, the mechanism by which SP1 regulates OP progression remains unclear. OBJECTIVE: This study investigated the mechanism underlying the function of SP1 in OP. METHODS: SAMP6 mice were used to establish an in vivo model of age-dependent OP, and BALB/c mice were used as controls. BMSCs were extracted from two subtypes of mice. Hematoxylin and eosin staining were performed to mark the intramedullary trabecular bone structure to evaluate histological changes. ChIP assay was used to assess the targeted regulation between SP1 and miR-133a-3p. The binding sites between MAPK3 and miR-133a-3p were verified using a dual-luciferase reporter assay. The mRNA levels of miR-133a-3p and MAPK3 were detected using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The protein expression of SP1, MAPK3, Colla1, OCN, and Runx2 was examined using Western blotting. Alkaline phosphatase (ALP) kit and Alizarin Red S staining were used to investigate ALP activity and mineralized nodules, respectively. RESULTS: The levels of SP1 and miR-133a-3p were upregulated, whereas the expression of MAPK3 was downregulated in BMSCs from SAMP6 mice, and miR-133a-3p inhibitor accelerated osteogenic differentiation in BMSCs. SP1 directly targeted miR-133a-3p, and MAPK3 was the downstream mRNA of miR-133a-3p. Mechanically, SP1 accelerated osteogenic differentiation in BMSCs via transcriptional mediation of the miR-133a-3p/MAPK3 axis. CONCLUSION: SP1 regulates osteogenic differentiation by mediating the miR-133a-3p/MAPK3 axis, which would shed new light on strategies for treating senile OP.

The DACH1 gene is frequently deleted in prostate cancer, restrains prostatic intraepithelial neoplasia, decreases DNA damage repair, and predicts therapy responses.

Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities. The DACH1 gene encodes a winged helix/Forkhead DNA-binding protein that competes for binding to FOXM1 sites. Herein, DACH1 gene deletion within the 13q21.31-q21.33 region occurs in up to 18% of human PCa and was associated with increased AR activity and poor prognosis. In prostate OncoMice, prostate-specific deletion of the Dach1 gene enhanced prostatic intraepithelial neoplasia (PIN), and was associated with increased TGFß activity and DNA damage. Reduced Dach1 increased DNA damage in response to genotoxic stresses. DACH1 was recruited to sites of DNA damage, augmenting recruitment of Ku70/Ku80. Reduced Dach1 expression was associated with increased homology directed repair and resistance to PARP inhibitors and TGFß kinase inhibitors. Reduced Dach1 expression may define a subclass of PCa that warrants specific therapies.

The DACH1 gene is frequently deleted in prostate cancer, restrains prostatic intraepithelial neoplasia, decreases DNA damage repair, and predicts therapy responses.

Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities. The DACH1 gene encodes a winged helix/Forkhead DNA-binding protein that competes for binding to FOXM1 sites. Herein, DACH1 gene deletion within the 13q21.31-q21.33 region occurs in up to 18% of human PCa and was associated with increased AR activity and poor prognosis. In prostate OncoMice, prostate-specific deletion of the Dach1 gene enhanced prostatic intraepithelial neoplasia (PIN), and was associated with increased TGFb activity and DNA damage. Reduced Dach1 increased DNA damage in response to genotoxic stresses. DACH1 was recruited to sites of DNA damage, augmenting recruitment of Ku70/Ku80. Reduced Dach1 expression was associated with increased homology directed repair and resistance to PARP inhibitors and TGFb kinase inhibitors. Reduced Dach1 expression may define a subclass of PCa that warrants specific therapies.

Arctigenin impairs UBC12 enzyme activity and cullin neddylation to attenuate cancer cells.

Neddylation is a type of posttranslational protein modification that has been observed to be overactivated in various cancers. UBC12 is one of two key E2 enzymes in the neddylation pathway. Reports indicate that UBC12 deficiency may suppress lung cancer cells, such that UBC12 could play an important role in tumor progression. However, systematic studies regarding the expression profile of UBC12 in cancers and its relationship to cancer prognosis are lacking. In this study, we comprehensively analyzed UBC12 expression in diverse cancer types and found that UBC12 is markedly overexpressed in most cancers (17/21), a symptom that negatively correlates with the survival rates of cancer patients, including gastric cancer. These results demonstrate the suitability of UBC12 as a potential target for cancer treatment. Currently, no effective inhibitor targeting UBC12 has been discovered. We screened a natural product library and found, for the first time, that arctigenin has been shown to significantly inhibit UBC12 enzyme activity and cullin neddylation. The inhibition of UBC12 enzyme activity was newly found to contribute to the effects of arctigenin on suppressing the malignant phenotypes of cancer cells. Furthermore, we performed proteomics analysis and found that arctigenin intervened with cullin downstream signaling pathways and substrates, such as the tumor suppressor PDCD4. In summary, these results demonstrate the importance of UBC12 as a potential therapeutic target for cancer treatment, and, for the first time, the suitability of arctigenin as a potential compound targeting UBC12 enzyme activity. Thus, these findings provide a new strategy for inhibiting neddylation-overactivated cancers.

Advances in targeted therapy for osteosarcoma based on molecular classification.

Osteosarcoma, a highly malignant tumor, is characterized by widespread and recurrent chromosomal and genetic abnormalities. In recent years, a number of elaborated sequencing analyses have made it possible to cluster the osteosarcoma based on the identification of candidate driver genes and develop targeted therapy. Here, we reviewed recent next-generation genome sequencing studies and advances in targeted therapies for osteosarcoma based on molecular classification. First, we stratified osteosarcomas into ten molecular subtypes based on genetic changes. And we analyzed potential targeted therapies for osteosarcoma based on the identified molecular subtypes. Finally, the development of targeted therapies for osteosarcoma investigated in clinical trials were further summarized and discussed. Therefore, we indicated the importance of molecular classification on the targeted therapy for osteosarcoma. And the stratification of patients based on the genetic characteristics of osteosarcoma will help to obtain a better therapeutic response to targeted therapies, bringing us closer to the era of personalized medicine.