Ctrp4, a new adipokine, promotes the differentiation of osteoblasts.

Recent evidence suggests that adipokines are involved in the regulation of bone metabolism. Ctrp4 is a newly discovered member of the adipokine CTRP family. Studies have shown that Ctrp4 is involved in the regulation of tumor cell inflammatory signaling pathways and acts on the hypothalamus to regulate food intake, but its role in osteoblasts is not yet clear. In this study, we found that the expression of Ctrp4 in bone tissue was significantly decreased in the tail-suspended mouse, while that in ovariectomized-simulated osteoporosis mice decreased similarly, indicating that Ctrp4 was involved in osteogenesis regulation. We further isolated Alp-positive osteoblasts from the femur of tail-suspended rats and confirmed that the expression of Ctrp4, Bglap and Alp was down-regulated in the process of bone loss caused by tail suspension. In the process of inducing osteoblastic differentiation in vitro, Ctrp4 interfering significantly inhibited the expression of Alp and Bglap. In addition, inhibition of Ctrp4 resulted in decreased alkaline phosphatase expression and less alizarin red staining, indicating that Ctrp4 promoted osteogenic differentiation and osteoblasts mineralization. In conclusion, our results suggest that Ctrp4 is involved in bone metabolism regulation and promotes osteoblast differentiation, which may become a potential target for future intervention in bone metabolic diseases.

Tumor-suppressive miR-145 co-repressed by TCF4-ß-catenin and PRC2 complexes forms double-negative regulation loops with its negative regulators in colorectal cancer.

The frequently dysregulated Wnt/ß-catenin signaling in different malignancies, by activation of its own or orchestration with other co-factors, regulates various oncogenic or tumor-suppressive genes. Among these genes, miRNAs, which are negative posttranscriptional regulators, are also embedded in the Wnt signaling network. Different from the Wnt-induced oncogenic miRNAs, the specific mechanism underlying the Wnt-repressed tumor-suppressive miRNAs is much less understood. In our study, firstly by analyzing a ChIP-seq dataset against TCF4, the core transcription factor for initiation of Wnt signaling in colorectal cancer (CRC) cells, we screened out several tumor-suppressive miRNAs potentially regulated by Wnt signaling. Then through siRNA-mediated knock-down tests and protein and chromatin immunoprecipitations, we found the TCF4-ß-catenin complex can recruit the histone trimethylation complex PRC2 as a co-repressor while binding to the TCF4-binding element (TBE) in the promoter regions of miR-145, miR-132 and miR-212. Thus, upon Wnt signaling activation, the PRC2-mediated trimethylation of histone H3 at lysine 27 increases at these promoter regions, leading to decreased miRNA levels. Furthermore, we found that by targeting TCF4 and SUZ12, the key components of the negative regulation complexes, the tumor-suppressive miR-145 co-repressed by Wnt signaling and histone trimethylation, forms double-negative regulation loops with its negative regulators in CRC cells. And the inverse associations between miR-145 and its targets/negative regulators have also been demonstrated in nude mice and clinical samples. Collectively, we elucidated the detailed molecular mechanism of how dysregulated Wnt/ß-catenin signaling and tumor-suppressive miRNAs reciprocally regulate each other in CRC cells.

Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor.

Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunogenicity. As heterodimerization and signaling partners for human epidermal growth factor receptor 2 (HER2), HER3/HER4 has been implicated in tumorigenic signaling and therapeutic resistance of breast cancer. In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1ß (HRG1ß) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors. Our results showed that HRG1ß-CAR was successfully constructed, and T cells were transduced at a rate of 50%. The CAR-T cells specifically recognized and killed HER3-overexpressing breast cancer cells SK-BR-3 and BT-474 in vitro, and displayed potent tumoricidal effect on SK-BR-3 xenograft tumor models. Our results suggest that HRG1ß-based CAR-T cells effectively suppress breast cancer driven by HER family receptors, and may provide a novel strategy to overcome cancer resistance to HER2-targeted therapy.

Combined Treatment with Valproic Acid and 5-Aza-2'-Deoxycytidine Synergistically Inhibits Human Clear Cell Renal Cell Carcinoma Growth and Migration.

BACKGROUND Histone acetylation and DNA methylation are important mammalian epigenetic modifications that participate in the regulation of gene expression. Because dysregulation of histone deacetylase and DNA methyltransferases are hallmarks of malignancy, they have become promising therapeutic targets. In this study, we explored the anti-tumor activity of valproic acid (VPA), a histone deacetylase inhibitor (HDACi) and 5-Aza-2'-deoxycytidine (5-Aza), an inhibitor of DNA methyltransferases, on renal cell carcinoma (RCC) cell lines 786-O and 769-P. MATERIAL AND METHODS The cell proliferation was detected by xCELLigence RTCA DP Instrument, viability by CCK8 assay, cell apoptosis and cell cycle by flow cytometry, and cell migration by wound healing assay, Transwell assay and xCELLigence RTCA DP Instrument. RESULTS We discovered that VPA and 5-Aza could individually induce decreased viability and have an inhibitory effect on the proliferation of 786-O and 769-P cells. This anti-growth effect was more pronounced when the cells were treated with both VPA and 5-Aza. The combination of VPA and 5-Aza also elicited more apoptosis and produced more cell cycle arrest in the G1 phase for both cell lines. On the other hand, treatment of RCC cells with VPA, 5-Aza, or a combination of both resulted in slow wound healing and impaired migration. CONCLUSIONS These findings clearly demonstrated that VPA combined with 5-Aza could significantly increase anti-RCC effects by inhibiting cellular proliferation, inducing apoptosis, promoting cell cycle arrest and prohibiting the migration of human RCC cells.

MYSM1 Is Essential for Maintaining Hematopoietic Stem Cell (HSC) Quiescence and Survival.

BACKGROUND Histone H2A deubiquitinase MYSM1 has recently been shown to be essential for hematopoiesis and hematopoietic stem cell (HSC) function in both mice and humans. However, conventional MYSM1 knockouts cause partial embryonic lethality and growth retardation, and it is difficult to convincingly remove the effects of environmental factors on HSC differentiation and function. MATERIAL AND METHODS MYSM1 conditional knockout (cKO) mice were efficiently induced by using the Vav1-cre transgenic system. The Vav-Cre MYSM1 cKO mice were then analyzed to verify the intrinsic role of MYSM1 in hematopoietic cells. RESULTS MYSM1 cKO mice were viable and were born at normal litter sizes. At steady state, we observed a defect in hematopoiesis, including reduced bone marrow cellularity and abnormal HSC function. MYSM1 deletion drives HSCs from quiescence into rapid cycling, and MYSM1-deficient HSCs display impaired engraftment. In particular, the immature cycling cKO HSCs have elevated reactive oxygen species (ROS) levels and are prone to apoptosis, resulting in the exhaustion of the stem cell pool during stress response to 5-FU. CONCLUSIONS Our study using MYSM1 cKO mice confirms the important role of MYSM1 in maintaining HSC quiescence and survival.

Knockdown of COUP-TFII inhibits cell proliferation and induces apoptosis through upregulating BRCA1 in renal cell carcinoma cells.

COUP-TFII belongs to the nuclear receptor family, which is highly expressed in many kinds of tumors. Previous studies have shown that COUP-TFII can promote tumor progression through regulating tumor angiogenesis and cell proliferation and migration of certain cancer cells. However, the function of COUP-TFII in renal cell carcinoma (RCC) is not clear. Here, we showed that clinical RCC tumor tissues showed much higher COUP-TFII expression level than adjacent normal tissues. When COUP-TFII was knocked down in RCC 769-P and 786-O cells by siRNA or shRNA-expressing lentivirus, the cell proliferation was markedly inhibited, and apoptosis increased. Moreover, the tumor growth of COUP-TFII knockdown 769-P and 786-O xenografts in nude mice was also obviously inhibited. Using qRT-PCR and Western blot, we showed that the expression of the tumor suppressor gene BRCA1 was upregulated in COUP-TFII knockdown cells. Simultaneously knockdown of BRCA1 and COUP-TFII partially rescued the inhibited cell proliferation and increased apoptosis in COUP-TFII single knockdown cells. These results indicate that COUP-TFII may play an oncogenic role in RCC, and COUP-TFII may promote tumor progression through inhibiting BRCA1.

High expression of CREPT promotes tumor growth and is correlated with poor prognosis in colorectal cancer.

CREPT (cell cycle-related and expression elevated protein in tumor) is highly expressed in many kinds of cancer, and has been shown to be prognostic in certain cancers. However, the clinical significance of CREPT in colorectal cancer (CRC) has not been sufficiently investigated. In this study, we examined the CREPT expression in 225 clinical CRC tissues and paired adjacent normal tissues, and analyzed the correlation between CREPT expression and other clinicopathological features. We also evaluated the biological function of CREPT both in vitro and in vivo using knockdown or overexpressing CRC cells. Our results showed that CREPT expressed in 175 of 225 (77.8%) CRC patients and the CREPT expression was significantly associated with tumor differentiation (P = 0.000), Dukes' stages (P = 0.013) and metastasis (P = 0.038). Patients with high CREPT expression tended to have shorter survival time. Multivariate analysis showed that positive CREPT expression can be used as an independent predictor for CRC prognosis. CREPT knockdown cells showed inhibited cell proliferation and arrested cell cycle, while CREPT overexpressing cells showed increased proliferation and promoted cell cycle. In addition, CREPT overexpression significantly promoted tumor growth in vivo. Mechanism study showed that CREPT may regulate cell proliferation and cell cycle through the regulation on cyclin D3, CDK4 and CDK6.

MiR-221/222 promote human glioma cell invasion and angiogenesis by targeting TIMP2.

miR-221/222 are two highly homologous microRNAs that are frequently upregulated in solid tumors. However, the effects of miR-221/222 in malignant gliomas have not been investigated thoroughly. In this study, we found that miR-221/222 were significantly upregulated in human glioma samples and glioma cell lines. Both gain- and loss-of-function studies showed that miR-221/222 regulate cell proliferation, the cell cycle and apoptosis, in addition to, invasion, metastasis, and angiogenesis in glioma cell lines. Subsequent investigations revealed that TIMP2 is a direct target of miR-221/222, and overexpression of TIMP2 reduced the miR-221/222-mediated invasion, metastasis, and angiogenesis of glioma cells. Taken together, our results suggest that the suppression of miR-221/222 may be a feasible approach for inhibiting the malignant behaviors of glioma.

MiR-200c suppresses TGF-ß signaling and counteracts trastuzumab resistance and metastasis by targeting ZNF217 and ZEB1 in breast cancer.

Resistance to trastuzumab and concomitantly distal metastasis are leading causes of mortality in HER2-positive breast cancers, the molecular basis of which remains largely unknown. Here, we generated trastuzumab-resistant breast cancer cells with increased tumorigenicity and invasiveness compared with parental cells, and observed robust epithelial-mesenchymal transition (EMT) and consistently elevated TGF-ß signaling in these cells. MiR-200c, which was the most significantly downregulated miRNA in trastuzumab-resistant cells, restored trastuzumab sensitivity and suppressed invasion of breast cancer cells by concurrently targeting ZNF217, a transcriptional activator of TGF-ß, and ZEB1, a known mediator of TGF-ß signaling. Given the reported backward inhibition of miR-200c by ZEB1, ZNF217 also exerts a feedback suppression of miR-200c via TGF-ß/ZEB1 signaling. Restoration of miR-200c, silencing of ZEB1 or ZNF217 or blockade of TGF-ß signaling increased trastuzumab sensitivity and suppressed invasiveness of breast cancer cells. Therefore, our study unraveled nested regulatory circuits of miR-200c/ZEB1 and miR-200c/ZNF217/TGF-ß/ZEB1 in synergistically promoting trastuzumab resistance and metastasis of breast cancer cells. These findings provide novel insights into the common role of EMT and related molecular machinery in mediating the malignant phenotypes of breast cancers.

A novel MYC-ZNF706-SLC7A11 regulatory circuit contributes to cancer progression and redox balance in human hepatocellular carcinoma.

The oncogenic potential of chromosome 8q22 copy number gain in liver cancer remains to be depicted. Here, we report that ZNF706, encoded by a gene mapped to chromosome 8q22, is a C2H2-type zinc finger protein. However, the biological function and mechanism of ZNF706 have been poorly investigated. Clinically, ZNF706 expression was elevated in hepatocellular carcinoma (HCC), and high ZNF706 expression was associated with unfavorable survival in HCC patients. Functional experiments revealed that ZNF706 knockdown inhibited HCC progression both in vitro and in vivo. RNA sequencing (RNA-seq) and chromatin immunoprecipitation-based deep sequencing (ChIP-seq) revealed that mechanistically, ZNF706 is a crucial ferroptosis regulator and that SLC7A11 is a critical target of ZNF706. In addition, ZNF706 knockdown inhibited SLC7A11 expression, increased lipid peroxidation, and promoted ferroptosis. Further analysis revealed that ZNF706 is a novel direct target transcriptionally activated by MYC in HCC cells. Importantly, MYC depletion reduced SLC7A11-mediated redox homeostasis, and this effect was reversed by ZNF706 reexpression. Collectively, our data demonstrate that ZNF706 is a potential oncogene in liver cancer and functions as a ferroptosis regulator by modulating SLC7A11 expression, constituting a potential therapeutic target for HCC.

[In vitro and in vivo validation of cytotoxicity of targeting human epidermal growth factor receptor-2 chimeric antigen receptor T (HER2-CAR-T) cells].

Objective To evaluate the toxicology of targeting human epidermal growth factor receptor-2 chimeric antigen receptor T (HER2-CAR-T) cells and to provide a safety basis for the clinical evaluation of HER2-CAR-T cell therapy. Methods The recombinant lentiviral vector was used to generate HER2-CAR-T cells. Soft agar colony formation assay was used to observe the colony formation of HER2-CAR-T cells, and the colony formation rate was statistically analyzed. The HER2-CAR-T cell suspension was co-incubated with rabbit red blood cell suspension, and the hemolysis of red blood cells was evaluated by direct observation and microplate reader detection. The HER2-CAR-T cell preparation was injected into the ear vein of male New Zealand rabbits, and the stimulating effect of HER2-CAR-T cells on the blood vessels of the animals was observed by staining of tissue sections. The vesicular stomatitis virus envelope glycoprotein (VSV-G) gene of pMD 2.G vector was used as the target sequence, and the safety of the lentiviral vector was verified by real-time fluorescence quantitative PCR. The heart, liver, lung, and kidney of mice receiving HER2-CAR-T cell infusion were collected, and the lesions were observed by HE staining. Results The HER2-CAR-T cells were successfully prepared. These cells did not exhibit soft agar colony formation ability in vitro, and the HER2-CAR-T cell preparation did not cause hemolysis in New Zealand rabbit red blood cells. After the infusion of HER2-CAR-T cells into the ear vein of New Zealand rabbits, no obvious vascular stimulation response was found, and no specific amplification of VSV-G was detected. No obvious lesions were found in the heart, liver, lung and kidney tissues of the treatment group. Conclusion The prepared HER2-CAR-T cells have reliable safety.

Interaction between HLA-G and NK cell receptor KIR2DL4 orchestrates HER2-positive breast cancer resistance to trastuzumab.

Despite the successful use of the humanized monoclonal antibody trastuzumab (Herceptin) in the clinical treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer, the frequently occurring drug resistance remains to be overcome. The regulatory mechanisms of trastuzumab-elicited immune response in the tumor microenvironment remain largely uncharacterized. Here, we found that the nonclassical histocompatibility antigen HLA-G desensitizes breast cancer cells to trastuzumab by binding to the natural killer (NK) cell receptor KIR2DL4. Unless engaged by HLA-G, KIR2DL4 promotes antibody-dependent cell-mediated cytotoxicity and forms a regulatory circuit with the interferon-γ (IFN-γ) production pathway, in which IFN-γ upregulates KIR2DL4 via JAK2/STAT1 signaling, and then KIR2DL4 synergizes with the Fcγ receptor to increase IFN-γ secretion by NK cells. Trastuzumab treatment of neoplastic and NK cells leads to aberrant cytokine production characterized by excessive tumor growth factor-ß (TGF-ß) and IFN-γ, which subsequently reinforce HLA-G/KIR2DL4 signaling. In addition, TGF-ß and IFN-γ impair the cytotoxicity of NK cells by upregulating PD-L1 on tumor cells and PD-1 on NK cells. Blockade of HLA-G/KIR2DL4 signaling improved the vulnerability of HER2-positive breast cancer to trastuzumab treatment in vivo. These findings provide novel insights into the mechanisms underlying trastuzumab resistance and demonstrate the applicability of combined HLA-G and PD-L1/PD-1 targeting in the treatment of trastuzumab-resistant breast cancer.

MYSM1 inhibits human colorectal cancer tumorigenesis by activating miR-200 family members/CDH1 and blocking PI3K/AKT signaling.

BACKGROUND: Histone epigenetic modification disorder is an important predisposing factor for the occurrence and development of many cancers, including colorectal cancer (CRC). The role of MYSM1, a metalloprotease that deubiquitinates monoubiquitinated histone H2A, in colorectal cancer was identified to evaluate its potential clinical application value. METHODS: MYSM1 expression levels in CRC cell lines and tumor tissues were detected, and their associations with patient survival rate and clinical stage were analyzed using databases and tissue microarrays. Gain- and loss-of-function studies were performed to identify the roles of MYSM1 in CRC cell proliferation, apoptosis, cell cycle progression, epithelial-mesenchymal transition (EMT) and metastasis in vitro and in vivo. ChIP, rescue assays and signal pathway verification were conducted for mechanistic study. Immunohistochemistry (IHC) was used to further assess the relationship of MYSM1 with CRC diagnosis and prognosis. RESULTS: MYSM1 was significantly downregulated and was related to the overall survival (OS) of CRC patients. MYSM1 served as a CRC suppressor by inducing apoptosis and inhibiting cell proliferation, EMT, tumorigenic potential and metastasis. Mechanistically, MYSM1 directly bound to the promoter region of miR-200/CDH1, impaired the enrichment of repressive H2AK119ub1 modification and epigenetically enhanced miR-200/CDH1 expression. Testing of paired CRC patient samples confirmed the positive regulatory relationship between MYSM1 and miR-200/CDH1. Furthermore, silencing MYSM1 stimulated PI3K/AKT signaling and promoted EMT in CRC cells. More importantly, a positive association existed between MYSM1 expression and a favorable CRC prognosis. CONCLUSIONS: MYSM1 plays essential suppressive roles in CRC tumorigenesis and is a potential target for reducing CRC progression and distant metastasis.

MiR-140-3p inhibits natural killer cytotoxicity to human ovarian cancer via targeting MAPK1.

Natural killer (NK) cells have pivotal role in immunotherapy of human ovarian cancer (OC). Although microRNAs (miRNAs) participate in dysfunction of NK cells, how and whether miR-140-3p regulates cytotoxicity of NK cells in OC are uncertain. miR-140-3p and mitogen activated protein kinase 1 (MAPK1) abundances were examined via quantitative real-time polymerase chain reaction or western blot. Tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) abundances were examined via enzyme linked immunosorbent assay. NK cytotoxicity to OC was evaluated via lactate dehydrogenase release. The relevance of miR-140-3p and MAPK1 was proved via luciferase activity analysis. Murine xenograft experiment was applied to assess the function of miR-140-3p on NK cytotoxicity. miR-140-3p was elevated and MAPK1 was declined in NK cells from OC patients, while the levels were reversed after treatment of interleukin-2 (IL-2). MiR-140-3p addition mitigated IFN-γ and TNF-α production induced via IL-2 as well as NK-92 cytotoxicity to OC cells. Additionally, MAPK1 was negatively regulated via miR-140-3p and ablated the influence of miR140-3p on cytotoxicity, cytokines levels. Besides, miR-140-3p enrichment facilitated tumor growth via suppressing function of NK cells in a xenograft model. miR-140-3p suppressed NK cytotoxicity to OC cells via mediating MAPK1, indicating a new avenue of ameliorating NK cells function for OC treatment.

Re-recognition of pseudogenes: From molecular to clinical applications.

Pseudogenes were initially regarded as "nonfunctional" genomic elements that did not have protein-coding abilities due to several endogenous inactivating mutations. Although pseudogenes are widely expressed in prokaryotes and eukaryotes, for decades, they have been largely ignored and classified as gene "junk" or "relics". With the widespread availability of high-throughput sequencing analysis, especially omics technologies, knowledge concerning pseudogenes has substantially increased. Pseudogenes are evolutionarily conserved and derive primarily from a mutation or retrotransposon, conferring the pseudogene with a "gene repository" role to store and expand genetic information. In contrast to previous notions, pseudogenes have a variety of functions at the DNA, RNA and protein levels for broadly participating in gene regulation to influence the development and progression of certain diseases, especially cancer. Indeed, some pseudogenes have been proven to encode proteins, strongly contradicting their "trash" identification, and have been confirmed to have tissue-specific and disease subtype-specific expression, indicating their own value in disease diagnosis. Moreover, pseudogenes have been correlated with the life expectancy of patients and exhibit great potential for future use in disease treatment, suggesting that they are promising biomarkers and therapeutic targets for clinical applications. In this review, we summarize the natural properties, functions, disease involvement and clinical value of pseudogenes. Although our knowledge of pseudogenes remains nascent, this field deserves more attention and deeper exploration.

Ring finger protein 2 promotes colorectal cancer progression by suppressing early growth response 1.

Ring finger protein 2 (RNF2) is an important component of polycomb repressive complex 1. RNF2 is upregulated in many kinds of tumors, and elevated RNF2 expression is associated with a poor prognosis in certain cancers. To assess the function of RNF2 in colorectal cancer, we examined RNF2 protein levels in 313 paired colorectal cancer tissues and adjacent normal tissues. We then analyzed the association of RNF2 expression with the patients' clinicopathologic features and prognoses. RNF2 expression was upregulated in colorectal cancer tissues and was associated with the tumor differentiation status, tumor stage and prognosis. In colorectal cancer cell lines, downregulation of RNF2 inhibited cell proliferation and induced apoptosis. Gene microarray analysis revealed that early growth response 1 (EGR1) was upregulated in RNF2-knockdown cells. Knocking down EGR1 partially reversed the inhibition of cell proliferation and the induction of apoptosis in RNF2-knockdown cells. RNF2 was enriched at the EGR1 promoter, where it mono-ubiquitinated histone H2A, thereby inhibiting EGR1 expression. These results indicate that RNF2 is oncogenic in colorectal cancer and may promote disease progression by inhibiting EGR1 expression. RNF2 is thus a potential prognostic marker and therapeutic target in colorectal cancer.

Circular RNAs in immune responses and immune diseases.

Circular RNAs (circRNAs) are novel clusters of endogenous noncoding RNAs (ncRNAs) that are widely expressed in eukaryotic cells. In contrast to the generation of linear RNA transcripts, circRNAs undergo a "back-splicing" process to form a continuous, covalently closed, stable loop structure without 5' or 3' polarities and poly (A) tails during posttranscriptional modification. Due to the widespread availability of several technologies, especially high-throughput RNA sequencing, numerous circRNAs have been discovered not only in mammals but also in plants and insects. Notably, due to their abilities to serve as microRNA (miRNA) "sponges", miRNA "reservoirs", regulate gene expression and encode proteins, circRNAs participate in the development and progression of different immune responses and immune diseases by enriching various forms of epigenetic modification. CircRNAs have been demonstrated to be expressed in a tissue-specific and pathogenesis-related manner during the occurrence of multiple immune diseases. Additionally, because of their circular configurations, expression in blood and peripheral tissues and coexistence with exosomes, circRNAs show inherent conservation along with environmental resistance stability and may be regarded as potential biomarkers or therapeutic targets for some immune diseases. In this review, we summarize the characteristics, functions and mechanisms of circRNAs and their involvement in immune responses and diseases. Although our knowledge of circRNAs remains preliminary, this field is worthy of deeper exploration and greater research efforts.

MYSM1-AR complex-mediated repression of Akt/c-Raf/GSK-3ß signaling impedes castration-resistant prostate cancer growth.

Epigenetic alterations that lead to dysregulated gene expression in the progression of castration-resistant prostate cancer (CRPC) remain elusive. Here, we investigated the role of histone deubiquitinase MYSM1 in the pathogenesis of prostate cancer (PCa). Tissues and public datasets of PCa were evaluated for MYSM1 levels. We explored the effects of MYSM1 on cell proliferation, senescence and viability both in vitro and in vivo. Integrative database analyses and co-immunoprecipitation assays were performed to elucidate genomic association of MYSM1 and MYSM1-involved biological interaction network in PCa. We observed that MYSM1 were downregulated in CRPC compared to localized prostate tumors. Knockdown of MYSM1 promoted cell proliferation and suppressed senescence of CRPC cells under condition of androgen ablation. MYSM1 downregulation enhanced the tumorigenic ability in nude mice. Integrative bioinformatic analyses of the significantly associated genes with MYSM1 revealed MYSM1-correlated pathways, providing substantial clues as to the role of MYSM1 in PCa. MYSM1 was able to bind to androgen receptor instead of increasing its expression and knockdown of MYSM1 resulted in activation of Akt/c-Raf/GSK-3ß signaling. Together, our findings indicate that MYSM1 is pivotal in CRPC pathogenesis and may be established as a potential target for future treatment.

UHRF1 promotes renal cell carcinoma progression through epigenetic regulation of TXNIP.

UHRF1 is an important epigenetic regulator that belongs to the UHRF family. Overexpression of UHRF1 has been found in many kinds of tumors and its overexpression is associated with poor prognosis and short survival in certain cancer types. However, its function in renal cell carcinoma (RCC) is not clear. Here we report that RCC tumor tissues had obviously higher UHRF1 expression than normal renal tissues. Downregulation of UHRF1 by siRNA or shRNA in RCC cell lines resulted in decreased cell viability, inhibited cell migration and invasion, and increased apoptosis. UHRF1 knockdown RCC xenografts also resulted in obviously inhibited tumor growth in vivo. After downregulation of UHRF1 in RCC cells, the expression of TXNIP was upregulated. In addition, after UHRF1 and TXNIP were simultaneously downregulated, cell viability and cell invasion increased, whereas cell apoptosis decreased compared with UHRF1 single downregulated cells. We also showed that UHRF1 could recruit HDAC1 to the TXNIP promoter and mediate the deacetylation of histone H3K9, resulting in the inhibition of TXNIP expression. Our results confirm that UHRF1 has oncogenic function in RCC and UHRF1 may promote tumor progression through epigenetic regulation of TXNIP. UHRF1 might be used as a therapeutic target for RCC treatment.

Expression of Prostate-Specific Membrane Antigen in Tumor-Associated Vasculature Predicts Poor Prognosis in Hepatocellular Carcinoma.

INTRODUCTION: Prostate-specific membrane antigen (PSMA) was originally found to be specifically expressed in normal prostate, and its expression was upregulated in almost all stages of prostate cancer. In recent years, PSMA was also found to be expressed in tumor-associated vasculature in many nonprostatic solid tumors. However, the expression pattern of PSMA in hepatocellular carcinoma (HCC) is not well studied. METHODS: In this study, we examined PSMA expression in 103 HCC tissues using immunohistochemical staining and analyzed the association between PSMA expression and other clinicopathological features and prognosis. RESULTS: Among the 103 cases, 27 cases (26%) showed PSMA expression in more than 50% of tumor-associated vasculature, 49 cases (48%) showed PSMA expression in less than 50% of vasculature, and 27 cases (26%) did not have detectable PSMA expression. Vascular PSMA expression was associated with several clinicopathological features, such as tumor stage, tumor differentiation, lymph node metastasis, and Ki-67 index. Furthermore, high vascular PSMA expression was also associated with poor prognosis in patients with HCC. Univariate and multivariate analyses showed that high vascular PSMA expression can be used as an independent prognostic marker for HCC. DISCUSSION: Our study provides the evidence that PSMA is specifically expressed in tumor-associated vasculature of HCC, and vascular PSMA expression may be used as a novel prognostic marker and a vascular therapeutic target for HCC.