Herbal formula Yangyinjiedu induces lung cancer cell apoptosis via activation of early growth response 1.

Traditional Chinese Medicine (TCM) has been extensively used in clinical practices and proven to be effective against cancer. However, the underlying mechanisms remain to be investigated. In this study, we examined the anticancer activities of Chinese herbal formula Yangyinjiedu (YYJD) and found that YYJD exhibits cytotoxicity against lung cancer cells. Transcriptome analysis indicated that 2178 genes were differentially expressed (P < 0.05) upon YYJD treatment, with 1464 being (67.2%) up-regulated. Among these, we found that the tumour suppressor early growth response 1 (EGR1) is the most activated. We demonstrated that EGR1 contributes to YYJD-induced apoptosis in A549. Through dissecting EGR1-associated transcriptional network, we identified 275 genes as EGR1 direct targets, some targets are involved in apoptosis. Lastly, we observed that YYJD enhances EGR1 expression and induces cell death in tumour xenografts. Collectively, these findings suggest that YYJD exerts its anticancer activities through EGR1 activation, thus providing the evidence for its potential clinical application for lung cancer patients.

Androgen promotes differentiation of PLZF+ spermatogonia pool via indirect regulatory pattern.

BACKGROUND: Androgen plays a pivotal role in spermatogenesis, accompanying a question how androgen acts on germ cells in testis since germ cells lack of androgen receptors (AR). Promyelocytic leukemia zinc-finger (PLZF) is essential for maintenance of undifferentiated spermatogonia population which is terminologically called spermatogonia progenitor cells (SPCs). AIMS: We aim to figure out the molecular connections between androgen and fates of PLZF+ SPCs population. METHOD: Immunohistochemistry was conducted to confirm that postnatal testicular germ cells lacked endogenous AR. Subsequently, total cells were isolated from 5 dpp (day post partum) mouse testes, and dihydrotestosterone (DHT) and/or bicalutamide treatment manifested that Plzf was indirectly regulated by androgen. Then, Sertoli cells were purified to screen downstream targets of AR using ChIP-seq, and gene silence and overexpression were used to attest these interactions in Sertoli cells or SPCs-Sertoli cells co-culture system. Finally, these connections were further verified in vivo using androgen pharmacological deprivation mouse model. RESULTS: Gata2 is identified as a target of AR, and ß1-integrin is a target of Wilms' tumor 1 (WT1) in Sertoli cells. Androgen signal negatively regulate ß1-integrin on Sertoli cells via Gata2 and WT1, and ß1-integrin on Sertoli cells interacts with E-cadherin on SPCs to regulate SPCs fates. CONCLUSION: Androgen promotes differentiation of PLZF+ spermatogonia pool via indirect regulatory pattern.

NUDT21 negatively regulates PSMB2 and CXXC5 by alternative polyadenylation and contributes to hepatocellular carcinoma suppression.

Alternative polyadenylation (APA) is an important post-transcriptional regulatory mechanism and involved in many diseases, including cancer. CFIm25, a subunit of the cleavage factor I encoded by NUDT21, is required for 3'RNA cleavage and polyadenylation. Although it has been recently reported to be involved in glioblastoma tumor suppression, its roles and the underlying functional mechanism remain unclear in other types of cancer. In this study, we characterized NUDT21 in hepatocellular carcinoma (HCC). Reduced expression of NUDT21 was observed in HCC tissue compared to adjacent non-tumorous compartment. HCC patients with lower NUDT21 expression have shorter overall and disease-free survival times than those with higher NUDT21 expression after surgery. Knockdown of NUDT21 promotes HCC cell proliferation, metastasis, and tumorigenesis, whereas forced expression of NUDT21 exhibits the opposite effects. We then performed global APA site profiling analysis in HCC cells and identified considerable number of genes with shortened 3'UTRs upon the modulation of NUDT21 expression. In particular, we further characterized the NUDT21-regulated genes PSMB2 and CXXC5. We found NUDT21 knockdown increases usage of the proximal polyadenylation site in the PSMB2 and CXXC5 3' UTRs, resulting in marked increase in the expression of PSMB2 and CXXC5. Moreover, knockdown of PSMB2 or CXXC5 suppresses HCC cell proliferation and invasion. Taken together, our study demonstrated that NUDT21 inhibits HCC proliferation, metastasis and tumorigenesis, at least in part, by suppressing PSMB2 and CXXC5, and thereby provided a new insight into understanding the connection of HCC suppression and APA machinery.

STAT3 is required for proliferation and exhibits a cell type-specific binding preference in mouse female germline stem cells.

LIF-mediated STAT3 signaling is critically involved in stem cells and development. However, its function in mouse female germline cells (FGSCs) remains elusive. In this study, we demonstrated that LIF-induced STAT3 activation contributes to the proliferation and undifferentiation maintenance of mouse FGSCs. Characterization of the STAT3-mediated transcriptional network by intersecting ChIP-seq and RNA-seq datasets revealed 405 direct target genes of STAT3, which are primarily involved in proliferation and germline development. In particular, we observed that STAT3 exhibits a FGSC-specific binding pattern when compared with mouse embryonic stem cells. Taken together, our study reported that the LIF-mediated STAT3 activation is actively involved in FGSCs and functions through a distinctive binding pattern across the FGSC genome. This cell-type specific binding preference provides an insight into understanding the genetic base for STAT3-driven cellular functions in germline stem cells.

Characterization of DNA Methylation Associated Gene Regulatory Networks During Stomach Cancer Progression.

DNA methylation plays a critical role in tumorigenesis through regulating oncogene activation and tumor suppressor gene silencing. Although extensively analyzed, the implication of DNA methylation in gene regulatory network is less characterized. To address this issue, in this study we performed an integrative analysis on the alteration of DNA methylation patterns and the dynamics of gene regulatory network topology across distinct stages of stomach cancer. We found the global DNA methylation patterns in different stages are generally conserved, whereas some significantly differentially methylated genes were exclusively observed in the early stage of stomach cancer. Integrative analysis of DNA methylation and network topology alteration yielded several genes which have been reported to be involved in the progression of stomach cancer, such as IGF2, ERBB2, GSTP1, MYH11, TMEM59, and SST. Finally, we demonstrated that inhibition of SST promotes cell proliferation, suggesting that DNA methylation-associated SST suppression possibly contributes to the gastric cancer progression. Taken together, our study suggests the DNA methylation-associated regulatory network analysis could be used for identifying cancer-related genes. This strategy can facilitate the understanding of gene regulatory network in cancer biology and provide a new insight into the study of DNA methylation at system level.

Integrative epigenomic analysis reveals unique epigenetic signatures involved in unipotency of mouse female germline stem cells.

BACKGROUND: Germline stem cells play an essential role in establishing the fertility of an organism. Although extensively characterized, the regulatory mechanisms that govern the fundamental properties of mammalian female germline stem cells remain poorly understood. RESULTS: We generate genome-wide profiles of the histone modifications H3K4me1, H3K27ac, H3K4me3, and H3K27me3, DNA methylation, and RNA polymerase II occupancy and perform transcriptome analysis in mouse female germline stem cells. Comparison of enhancer regions between embryonic stem cells and female germline stem cells identifies the lineage-specific enhancers involved in germline stem cell features. Additionally, our results indicate that DNA methylation primarily contributes to female germline stem cell unipotency by suppressing the somatic program and is potentially involved in maintenance of sexual identity when compared with male germline stem cells. Moreover, we demonstrate down-regulation of Prmt5 triggers differentiation and thus uncover a role for Prmt5 in maintaining the undifferentiated status of female germline stem cells. CONCLUSIONS: The genome-wide epigenetic signatures and the transcription regulators identified here provide an invaluable resource for understanding the fundamental features of mouse female germline stem cells.