Drug resistance is the main obstacle in the improvement of chemotherapeutic efficacy in glioblastoma. Previously, we showed that dehydroepiandrosterone (DHEA), one kind of androgen/neurosteroid, potentiates glioblastoma to acquire resistance through attenuating DNA damage. Androgen receptor (AR) activated by DHEA or other types of androgen was reported to promote drug resistance in prostate cancer. However, in DHEA-enriched microenvironment, the role of AR in acquiring resistance of glioblastoma remains unknown. In this study, we found that AR expression is significantly correlated with poor prognosis, and AR obviously induced the resistance to temozolomide (TMZ) treatment. Herein, we observed that ALZ003, a curcumin analog, induces FBXL2-mediated AR ubiquitination, leading to degradation. Importantly, ALZ003 significantly inhibited the survival of TMZ-sensitive and -resistant glioblastoma in vitro and in vivo. The accumulation of reactive oxygen species (ROS), lipid peroxidation and suppression of glutathione peroxidase (GPX) 4, which are characteristics of ferroptosis, were observed in glioblastoma cell after treatment of ALZ003. Furthermore, overexpression of AR prevented ferroptosis in the presence of GPX4. To evaluate the therapeutic effect in vivo, we transplanted TMZ-sensitive or -resistant U87MG cells into mouse brain followed by intravenous administration with ALZ003. In addition to inhibiting the growth of glioblastoma, ALZ003 significantly extended the survival period of transplanted mice, and significantly decreased AR expression in the tumor area. Taken together, AR potentiates TMZ resistance for glioblastoma, and ALZ003-mediated AR ubiquitination might open a new insight into therapeutic strategy for TMZ resistant glioblastoma.

MicroRNAs (miRNAs), small noncoding RNAs, can control gene expression by binding to their target genes for degradation and/or translational repression. Epigenetic mechanisms are defined as heritable changes in gene expression that do not involve coding sequence modifications. Both mechanisms play an important role in maintaining physiological functions and are also related to disease development. However, few studies report that miRNA‐mediated epigenetic regulations are involved in atherosclerosis. In the present study, oxidized low‐density lipoprotein (oxLDL) significantly increased primary human aortic smooth muscle cell (HASMC) migration through MMP‐2/MMP‐9 up‐regulation associated with decreased DNA methylation levels. Either mRNA or protein level of DNA methyltrans‐ferase 3b (DNMT3b) showed a dose‐dependent down‐regulation in oxLDL‐mediated HASMCs. Knockdown DNMT3b expression enhanced oxLDL‐induced DNAde‐methylation levels of MMP‐2/MMP‐9. The expression of miRNA‐29b (miR‐29b)' directly targeting DNMT3b, was up‐regulated by oxLDL treatment in a dose‐dependent manner. OxLDL‐mediated MMP‐2/MMP‐9 up‐regulation' DNMT3b down‐regulation' and DNA demethylation were all attenuated after knockdown miR‐29b expression by antagomiR‐29b. We find that oxLDL can up‐regulate miR‐29b expression' resulting in DNMT3b down‐regulation in HASMCs and epigenetically regulated MMP‐2/MMP‐9 genes involved in cell migration. These results show that miRNA‐mediated epigenetic regulation may be a novel mechanism in atherosclerosis.—Chen, K.‐C., Wang, Y.‐S., Hu, C.‐Y., Chang, W.‐C., Liao, Y C., Dai, C.‐Y., Juo, S.‐H. H. OxLDL up‐regulates microRNA‐29b, leading to epigenetic modifications of MMP‐2/MMP‐9 genes: a novel mechanism for cardiovascular diseases. FASEB J. 25, 1718–1728 (2011). www.fasebj.org

CCAAT/enhancer-binding protein delta (CEBPD) belongs to the CCAAT/enhancer-binding protein family, and these proteins function as transcription factors in many biological processes, including cell differentiation, motility, growth arrest, proliferation, cell death, metabolism and immune responses. The functional diversity of CEBPD depends, in part, on the cell type and cellular context, which indicates that CEBPD could interpret a variety of cues to adjust cellular responses in specific situations. Here, we review the regulation of the CEBPD gene and its function in response to inflammatory stimuli. We also address its effects in inflammation-related diseases through a discussion of its recently discovered downstream targets. Regarding to the previous discoveries and new insights in inflammation-associated diseases, suggesting CEBPD could also be a central gene in inflammation. Importantly, the results of this study indicate that the investigation of CEBPD could open a new avenue to help better understand the inflammatory response.

Loss of the maintenance of genetic material is a critical step leading to tumorigenesis. It was reported that overexpression of Aurora-A and the constitutive activation of the epidermal growth factor (EGF) receptor (EGFR) are implicated in chromosome instability. In this study, we examined that when cells treated with EGF result in centrosome amplification and microtubule disorder, which are critical for genetic instability. Interestingly, the expression of Aurora-A was also increased by EGF stimulus. An immunofluorescence assay indicated that EGF can induce the nuclear translocation of EGFR. Chromatin immunoprecipitation (ChIP) and re-ChIP assays showed significant EGF-induced recruitment of nuclear EGFR and signal transducer and activator of transcription 5 (STAT5) to the Aurora-A promoter. A co-immunoprecipitation assay further demonstrated that EGF induces nuclear interaction between EGFR and STAT5. A small interfering (si)RNA knockdown assay also showed that EGFR and STAT5 are indeed involved in EGF-increased Aurora-A gene expression. Altogether, this study proposes that the nuclear EGFR associates with STAT5 to bind and increase Aurora-A gene expression, which ultimately may lead to chromosome instability and tumorigenesis. The results also provide a novel linkage between the EGFR signaling pathway and overexpression of Aurora-A in tumorigenesis and chromosome instability.

Ca²⁺ signaling has been increasingly implicated in cancer invasion and metastasis, and yet, the underlying mechanisms remained largely unknown. In this paper, we report that STIM1- and Orai1-mediated Ca²⁺ oscillations promote melanoma invasion by orchestrating invadopodium assembly and extracellular matrix (ECM) degradation. Ca²⁺ oscillation signals facilitate invadopodial precursor assembly by activating Src. Disruption of Ca²⁺ oscillations inhibited invadopodium assembly. Furthermore, STIM1 and Orai1 regulate the proteolysis activity of individual invadopodia. Mechanistically, Orai1 blockade inhibited the recycling of MT1–matrix metalloproteinase (MMP) to the plasma membrane and entrapped MT1-MMP in the endocytic compartment to inhibit ECM degradation. STIM1 knockdown significantly inhibited melanoma lung metastasis in a xenograft mouse model, implicating the importance of this pathway in metastatic dissemination. Our findings provide a novel mechanism for Ca²⁺-mediated cancer cell invasion and shed new light on the spatiotemporal organization of store-operated Ca²⁺ signals during melanoma invasion and metastasis.

Tumor metastasis is the major cause of death among cancer patients, with >90% of cancer-related death attributable to the spreading of metastatic cells to secondary organs. Store-operated Ca²⁺ entry (SOCE) is the predominant Ca²⁺ entry mechanism in most cancer cells, and stromal interaction molecule 1 (STIM1) is the endoplasmic reticulum (ER) Ca²⁺ sensor for store-operated channels. Here we reported that the STIM1 was overexpressed in colorectal cancer (CRC) patients. STIM1 overexpression in CRC was significantly associated with tumor size, depth of invasion, lymph node metastasis status and serum levels of carcinoembryonic antigen. Furthermore, ectopic expression of STIM1 promoted CRC cell motility, while depletion of STIM1 with short hairpin RNA inhibited CRC cell migration. Our data further suggested that STIM1 promoted CRC cell migration through increasing the expression of cyclooxygenase-2 (COX-2) and production of prostaglandin E2 (PGE2). Importantly, ectopically expressed COX-2 or exogenous PGE2 were able to rescue migration defect in STIM1 knockdown CRC cells, and inhibition of COX-2 with ibuprofen and indomethacin abrogated STIM1-mediated CRC cell motility. In short, our data provided clinicopathological significance for STIM1 and SOCE in CRC progression, and implicated a role for COX-2 in STIM1-mediated CRC metastasis. Our studies also suggested a new approach to inhibit STIM1-mediated metastasis with COX-2 inhibitors.