High Mobility Group AT-hook 2 (HMGA2) is a nonhistone chromatin-binding protein which acts as a transcriptional regulating factor involved in gene transcription. In particular, overexpression of ...HMGA2 has been demonstrated to associate with neoplastic transformation and tumor progression in Colorectal Cancer (CRC). Thus, HMGA2 is a potential therapeutic target in cancer therapy. Heat Shock Protein 90 (Hsp90) is a chaperone protein required for the stability and function for a number of proteins that promote the growth, mobility, and survival of cancer cells. Moreover, it has shown strong positive connections were observed between Hsp90 inhibitors and CRC, which indicated their potential for use in CRC treatment by using combination of data mining and experimental designs. However, little is known about the effect of Hsp90 inhibition on HMGA2 protein expression in CRC. In this study, we tested the hypothesis that Hsp90 may regulate HMGA2 expression and investigated the relationship between Hsp90 and HMGA2 signaling. The use of the second-generation Hsp90 inhibitor, NVP-AUY922, considerably knocked down HMGA2 expression, and the effects of Hsp90 and HMGA2 knockdown were similar. In addition, Hsp90 knockdown abrogates colocalization of Hsp90 and HMGA2 in CRC cells. Moreover, the suppression of HMGA2 protein expression in response to NVP-AUY922 treatment resulted in ubiquitination and subsequent proteasome-dependant degradation of HMGA2. Furthermore, RNAi-mediated silencing of HMGA2 reduced the survival of CRC cells and increased the sensitivity of these cells to chemotherapy. Finally, we found that the NVP-AUY922-dependent mitigation of HMGA2 signaling occurred also through indirect reactivation of the tumor suppressor microRNA (miRNA), let-7a, or the inhibition of ERK-regulated HMGA2 involved in regulating the growth of CRC cells. Collectively, our studies identify the crucial role for the Hsp90-HMGA2 interaction in maintaining CRC cell survival and migration. These findings have significant implications for inhibition HMGA2-dependent tumorigenesis by clinically available Hsp90 inhibitors.
Akt activation has been implicated broadly in tumorigenesis, but the basis for its dysregulation in cancer cells is incompletely understood. In this study, we sought to clarify a regulatory role for ...the Akt-binding carboxy-terminal modulator protein (CTMP), which has been controversial. In evaluating CTMP expression in paired normal-tumor specimens of 198 patients with breast cancer, we found that CTMP was upregulated in breast tumors, where it was associated with poor patient survival. Notably, CTMP expression also correlated positively with Akt phosphorylation in breast cancer clinical specimens and cell lines. Furthermore, ectopic expression of CTMP promoted cell proliferation and enhanced the tumorigenic properties of estrogen-dependent breast cancer cells. This effect was correlated with increased sensitivity to insulin-induced Akt phosphorylation, which is mediated primarily by the phosphoinositide 3-kinase-Akt pathway. In contrast, short hairpin RNA-mediated silencing of endogenous CTMP decreased the proliferation of estrogen-dependent or estrogen-independent breast cancer cells. Mechanistic investigations defined the N-terminal domain of CTMP at amino acids 1 to 64 as responsible for Akt binding. Taken together, our results firmly corroborate the concept that CTMP promotes Akt phosphorylation and functions as an oncogenic molecule in breast cancer.
Rnf112 is a member of the RING finger protein family. The expression of Rnf112 is abundant in the brain and is regulated during brain development. Our previous study has revealed that Rnf112 can ...promote neuronal differentiation by inhibiting the progression of the cell cycle in cell models. In this study, we further revealed the important functions of Rnf112 in embryo development and in adult brain. Our data showed that most of the
Rnf112
−/−
embryos exhibited blood vascular defects and died in utero. Upon further investigation, we found that the survival rate of homozygous
Rnf112
knockout mice in 129/sv and C57BL/6 mixed genetic background was increased. The survived newborns of
Rnf112
−/−
mice manifested growth retardation as indicated by smaller size and a reduced weight. Although the overall organization of the brain did not appear to be severely affected in
Rnf112
−/−
mice, using in vivo 3D MRI imaging, we found that when compared to wild-type littermates, brains of
Rnf112
−/−
mice were smaller. In addition,
Rnf112
−/−
mice displayed impairment of brain functions including motor balance, and spatial learning and memory. Our results provide important aspects for the study of
Rnf112
gene functions.
The nucleolus is the cellular site of ribosomal (r)DNA transcription and ribosome biogenesis. The 58-kDa microspherule protein (MSP58) is a nucleolar protein involved in rDNA transcription and cell ...proliferation. However, regulation of MSP58-mediated rDNA transcription remains unknown. Using a yeast two-hybrid system with MSP58 as bait, we isolated complementary (c)DNA encoding Rad50-interacting protein 1 (RINT-1), as a MSP58-binding protein. RINT-1 was implicated in the cell cycle checkpoint, membrane trafficking, Golgi apparatus and centrosome dynamic integrity, and telomere length control. Both in vitro and in vivo interaction assays showed that MSP58 directly interacts with RINT-1. Interestingly, microscopic studies revealed the co-localization of MSP58, RINT-1, and the upstream binding factor (UBF), a rRNA transcription factor, in the nucleolus. We showed that ectopic expression of MSP58 or RINT-1 resulted in decreased rRNA expression and rDNA promoter activity, whereas knockdown of MSP58 or RINT-1 by siRNA exerted the opposite effect. Coexpression of MSP58 and RINT-1 robustly decreased rRNA synthesis compared to overexpression of either protein alone, whereas depletion of RINT-1 from MSP58-transfected cells enhanced rRNA synthesis. We also found that MSP58, RINT-1, and the UBF were associated with the rDNA promoter using a chromatin immunoprecipitation assay. Because aberrant ribosome biogenesis contributes to neoplastic transformation, our results revealed a novel protein complex involved in the regulation of rRNA gene expression, suggesting a role for MSP58 and RINT-1 in cancer development.
•RINT-1 is a novel MSP58-interacting protein.•RINT-1 is a nucleolar protein that suppresses ribosomal RNA gene transcription.•RINT-1 and MSP58 cooperate to suppress ribosomal RNA gene transcription.•RINT-1, MSP58, and UBF form a complex on the rDNA promoter.
PGC-1α, a major metabolic regulator of gluconeogenesis and lipogenesis, is strongly induced to coactivate Hepatitis B virus (HBV) gene expression in the liver of fasting mice. We found that 8-Br-cAMP ...and glucocorticoids synergistically induce PGC-1α and its downstream targets, including PEPCK and G6Pase. Also, HBV core promoter activity was synergistically enhanced by 8-Br-cAMP and glucocorticoids. Graptopetalum paraguayense (GP), a herbal medicine, is commonly used in Taiwan to treat liver disorders. Partially purified fraction of GP (named HH-F3) suppressed 8-Br-cAMP/glucocorticoid-induced G6Pase, PEPCK and PGC-1α expression and suppressed HBV core promoter activity. HH-F3 blocked HBV core promoter activity via inhibition of PGC-1α expression. Ectopically expressed PGC-1α rescued HH-F3-inhibited HBV surface antigen expression, HBV mRNA production, core protein levels, and HBV replication. HH-F3 also inhibited fatty acid synthase (FASN) expression and decreased lipid accumulation by down-regulating PGC-1α. Thus, HH-F3 can inhibit HBV replication, gluconeogenesis and lipogenesis by down-regulating PGC-1α. Our study indicates that targeting PGC-1α may be a therapeutic strategy for treatment of HBV infections. HH-F3 may have potential use for the treatment of chronic hepatitis B patients with associated metabolic syndrome.
The data in this article is related to the research article entitled, “Targeting of Multiple Oncogenic Signaling Pathways by Hsp90 Inhibitor Alone or in Combination with Berberine for Treatment of ...Colorectal Cancer” 1. Overexpression of survivin induces resistance to various anticancer therapies such as chemotherapy and radiation therapy in colorectal cancer (CRC) cells. To determine significant correlations of biological functions/pathways with survivin, 4567 significant genes were analyzed from the GEO DataSet (GSE21815) of CRC and these were overlaid onto a global molecular network developed from information contained in the Ingenuity Pathway Analysis (IPA) database. The data here present the most significant disease and disordered biological functions, significant molecular/cellular functions and significant categories in physiological development/system functions which were associated with CRC. The top 10 canonical signaling pathways associated with CRC were categorize in order based on the level of statistical significance.
Phosphorylation on certain Ser/Thr-Pro motifs is a major oncogenic mechanism. The conformation and function of phosphorylated Ser/Thr-Pro motifs are further regulated by the prolyl isomerase Pin1. ...Pin1 has been shown to be prevalently overexpressed in human breast cancer cell lines and cancer tissues and to play a critical role in the transformation of mammary epithelial cells by activating multiple oncogenic pathways. Pin1 expression was found to be an excellent independent prognostic marker in prostate cancer. However, little is known about Pin1 and its downstream targets beta-catenin and cyclin D1 expressions in human oral cancers. In the present study, we quantified Pin1 expression in 74 paired normal/tumor human oral cancer samples as well as oral cancer cell lines. Pin1 was overexpressed in oral squamous cell carcinoma (OSCC) and its level correlated with beta-catenin accumulation and cyclin D1 expression. Moreover, we examined Pin1 mRNA expression in OSCC and cancer cell lines by RT-PCR analysis. The results showed that there is concordance in the relationship between the Pin1 mRNA level and Pin1 protein expression. The up-regulation of Pin1 mRNA expression in tumor part when comparing with that in non-tumor part was in agreement with that of the Pin1 protein overexpressed in OSCC. In addition, we showed that the molecular and immunohistochemical profiles of Pin1 overexpression were associated with progression of OSCC. Taken together, these results indicate that Pin1 is a regulator of cyclin D1 expression in OSCC and might play a role in oral oncogenesis. The overexpression of Pin1 can be used as an indicator for pathological diagnosis of OSCC.
As lung cancer remains the leading cause of cancer deaths globally, characterizing the tumor molecular profiles is crucial to tailoring treatments for individuals at advanced stages. Cancer cells ...exhibit strong dependence on iron for their proliferation, and several iron-regulatory proteins have been proposed as either oncogenes or tumor suppressive genes. This study aims to evaluate the prospective therapeutic and prognostic values of the sideroflexin (SFXN) gene family, whose functions involve mitochondrial iron metabolism, in lung adenocarcinoma (LUAD). Differential expression analysis using TIMER and UALCAN tools was first employed to compare SFXNs expression levels between normal and LUAD tissues. Next, SFXNs’ prognostic values, biological significance, and potential as immunotherapy candidates were examined from GEPIA, cBioPortal, MetaCore, Cytoscape, and TIMER databases. It was found that all members of SFXN family, except SFXN3, were differentially expressed in LUAD compared to normal samples and within different stages of LUAD. Survival analysis then revealed SFXN1 to be related to worse overall survival outcome in patients with LUAD. Furthermore, several correlations between expression of SFXN1 and immune infiltration cells were discovered. To conclude, our study provides evidence of SFXN family gene’s relevance to the prognosis and immunotherapeutic targets of LUAD.
Breast cancer is the most common cancer type in females, and exploring the mechanisms of disease progression is playing a crucial role in the development of potential therapeutics. Pituitary ...tumor-transforming gene (PTTG) family members are well documented to be involved in cell-cycle regulation and mitosis, and contribute to cancer development by their involvement in cellular transformation in several tumor types. The critical roles of PTTG family members as crucial transcription factors in diverse types of cancers are recognized, but how they regulate breast cancer development still remains mostly unknown. Meanwhile, a holistic genetic analysis exploring whether PTTG family members regulate breast cancer progression via the cell cycle as well as the energy metabolism-related network is lacking. To comprehensively understand the messenger RNA expression profiles of PTTG proteins in breast cancer, we herein conducted a high-throughput screening approach by integrating information from various databases such as Oncomine, Kaplan-Meier Plotter, Metacore, ClueGo, and CluePedia. These useful databases and tools provide expression profiles and functional analyses. The present findings revealed that PTTG1 and PTTG3 are two important genes with high expressions in breast cancer relative to normal breast cells, implying their unique roles in breast cancer progression. Results of our coexpression analysis demonstrated that PTTG family genes were positively correlated with thiamine triphosphate (TTP), deoxycytidine triphosphate (dCTP) metabolic, glycolysis, gluconeogenesis, and cell-cycle related pathways. Meanwhile, through Cytoscape analyzed indicated that in addition to the metastasis markers AURKA, AURKB, and NDC80, many of the kinesin superfamily (KIF) members including KIFC1, KIF2C, KIF4A, KIF14, KIF20A, KIF23, were also correlated with PTTG family transcript expression. Finally, we revealed that high levels of PTTG1 and PTTG3 transcription predicted poor survival, which provided useful insights into prospective research of cancer associated with the PTTG family. Therefore, these members of the PTTG family would serve as distinct and essential prognostic biomarkers in breast cancer.
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