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1.
Am J Cancer Res ; 10(8): 2446-2463, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32905496

RESUMO

NFYA (nuclear transcription factor Y, subunit A) is a CCAAT-binding transcription factor. Accumulating evidence suggests that NFYA plays an important role in breast, ovarian, lung and gastric cancer. However, the role of NFYA in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, it was discovered that the expression of NFYA is elevated in tissues of ccRCC patient and high NFYA expression is linked to poor overall survival in ccRCC patient. Inhibition of G1/S cell cycle transition and decreased cell proliferation were observed upon NFYA knockdown in ccRCC cells. Moreover, further investigation revealed that NFYA binds directly to the promoter region of both CDK4 and cyclin D1 (CCND1) thus transactivating their expression, resulting in RB phosphorylation and the activation of subsequent E2F pathway activation. Taken together, these findings imply the oncogenic role of NFYA in ccRCC progression and its potential as a target for ccRCC therapy.

2.
Theranostics ; 10(22): 9984-10000, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32929329

RESUMO

Rationale: Neoadjuvant chemotherapy has become the standard treatment of locally advanced breast cancer. Antimicrotubule drugs and DNA-damaging drugs are the most popular medicines used for neoadjuvant chemotherapy. However, we are unable to predict which chemotherapeutic drug will benefit to an individual patient. PARK2 as a tumor suppressor in breast cancer has been reported. While the role of PARK2 in chemotherapy response remains unknown. In this study, we explore the impact of PARK2 on chemosensitivity in breast cancer. Methods: PARK2 expression in breast cancer patients with different neoadjuvant chemotherapeutic regimens was studied using immunohistochemistry. Data was correlated to disease-free survival (DFS), overall survival and pathologic complete response (pCR). The functional roles of PARK2 were demonstrated by a series of in vitro and in vivo experiments. Including mass spectrometry, Co-immunoprecipitation, isolation of subcellular fractionation, fluorescence microscopy, in vivo ubiquitination assay and luciferase analyses. Results: Highly expressed PARK2 predicted better response to antimicrotubule drugs-containing regimen associated with higher rate of pathologic complete response (pCR). In contrast, PARK2 expression did not predict response to the DNA-damaging drugs regimen. Following antimicrotubule drugs treatment, levels of PARK2 was upregulated due to the repression of STAT3-mediated transcriptional inhibition of PARK2. Moreover, overexpression of PARK2 specifically rendered cells more sensitive to antimicrotubule drugs, but not to DNA-damaging drugs. Depletion of PARK2 enhanced resistance to antimicrotubule drugs. Mechanistically, PARK2 markedly activated the mitochondrial pathway of apoptosis after exposure to antimicrotubule drugs. This occurred through downregulating the antiapoptotic protein, phospho-BCL-2. BCL-2 phosphorylation can be specifically induced by antimicrotubule drugs, whereas DNA-damaging drugs do not. Notably, PARK2 interacted with phospho-BCL-2 (Ser70) and promoted ubiquitination of BCL-2 in an E3 ligase-dependent manner. Hence, PARK2 significantly enhanced the chemosensitivity of antimicrotubule drugs both in vitro and in vivo, while loss-of-function PARK2 mutants did not. Conclusions: Our findings explained why PARK2 selectively confers chemosensitivity to antimicrotubule drugs, but not to DNA-damaging drugs. In addition, we identified PARK2 as a novel mediator of antimicrotubule drugs sensitivity, which can predict response of breast cancer patients to antimicrotubule drugs-containing regime.

3.
Am J Pathol ; 190(11): 2267-2281, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32805235

RESUMO

Liver fibrosis is an increasing health problem worldwide, for which no effective antifibrosis drugs are available. Although the involvement of aerobic glycolysis in hepatic stellate cell (HSC) activation has been reported, the role of pyruvate kinase M2 (PKM2) in liver fibrogenesis still remains unknown. We examined PKM2 expression and location in liver tissues and primary hepatic cells. The in vitro and in vivo effects of a PKM2 antagonist (shikonin) and its allosteric agent (TEPP-46) on liver fibrosis were investigated in HSCs and liver fibrosis mouse model. Chromatin immunoprecipitation sequencing and immunoprecipitation were performed to identify the relevant molecular mechanisms. PKM2 expression was significantly up-regulated in both mouse and human fibrotic livers compared with normal livers, and mainly detected in activated, rather than quiescent, HSCs. PKM2 knockdown markedly inhibited the activation and proliferation of HSCs in vitro. Interestingly, the PKM2 dimer, rather than the tetramer, induced HSC activation. PKM2 tetramerization induced by TEPP-46 effectively inhibited HSC activation, reduced aerobic glycolysis, and decreased MYC and CCND1 expression via regulating histone H3K9 acetylation in activated HSCs. TEPP-46 and shikonin dramatically attenuated liver fibrosis in vivo. Our findings demonstrate a nonmetabolic role of PKM2 in liver fibrosis. PKM2 tetramerization or suppression could prevent HSC activation and protects against liver fibrosis.


Assuntos
Células Estreladas do Fígado/enzimologia , Cirrose Hepática/enzimologia , Multimerização Proteica , Piruvato Quinase/metabolismo , Acetilação , Animais , Ciclina D1/metabolismo , Feminino , Células Estreladas do Fígado/patologia , Histonas/metabolismo , Humanos , Cirrose Hepática/patologia , Masculino , Camundongos , Compostos Orgânicos/farmacologia , Proteínas Proto-Oncogênicas c-myc/metabolismo
4.
J Cancer ; 10(27): 6837-6847, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31839818

RESUMO

Regulator of chromosome condensation 2 (RCC2), also known as TD-60, is an RCC1 family member and plays an essential role in mitosis. However, the roles of RCC2 in breast cancer are still unclear. In this study, RCC2 was found to exert oncogenic activities in breast cancer. Samples of breast cancer tissue revealed an increased level of RCC2 and a high level of RCC2 was associated with poor overall survival rate of breast cancer patients. Overexpression of RCC2 significantly enhanced cell proliferation and migration abilities of breast cancer cells in vitro and in vivo. Mechanistically, RCC2 induced epithelial-mesenchymal transition (EMT) through the activation of Wnt signaling pathway. Collectively, our study indicates that RCC2 contributes to breast cancer progression and functions as an important regulator of EMT through the activation of Wnt signaling.

5.
EMBO Rep ; 20(5)2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30940648

RESUMO

The bromodomain-containing protein 7 (BRD7) is a tumour suppressor protein with critical roles in cell cycle transition and transcriptional regulation. Whether BRD7 is regulated by post-translational modifications remains poorly understood. Here, we find that chemotherapy-induced DNA damage leads to the rapid degradation of BRD7 in various cancer cell lines. PARP-1 binds and poly(ADP)ribosylates BRD7, which enhances its ubiquitination and degradation through the PAR-binding E3 ubiquitin ligase RNF146. Moreover, the PARP1 inhibitor Olaparib significantly enhances the sensitivity of BRD7-positive cancer cells to chemotherapeutic drugs, while it has little effect on cells with low BRD7 expression. Taken together, our findings show that PARP1 induces the degradation of BRD7 resulting in cancer cell resistance to DNA-damaging agents. BRD7 might thus serve as potential biomarker in clinical trial for the prediction of synergistic effects between chemotherapeutic drugs and PARP inhibitors.


Assuntos
Antineoplásicos/farmacologia , Proteínas Cromossômicas não Histona/metabolismo , Dano ao DNA/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli ADP Ribosilação/efeitos dos fármacos , Células A549 , Linhagem Celular , Linhagem Celular Tumoral , DNA/metabolismo , Reparo do DNA/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Células MCF-7 , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Ligação Proteica/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/efeitos dos fármacos
6.
Mob DNA ; 10: 2, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30636978

RESUMO

[This corrects the article DOI: 10.1186/s13100-018-0139-y.].

7.
Mob DNA ; 9: 33, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30534207

RESUMO

Background: Similar to retro-/lenti- virus system, DNA transposons are useful tools for stable expression of exogenous genes in mammalian cells. Sleeping Beauty (SB) transposon has adopted for integrating genes into host genomes in recent studies. However, SB-derived vector system for proteins purifying/tracking and gene knockout are still not available. Results: In this study, we generated a series of vectors (termed as pSB vectors) containing Sleeping Beauty IRDR-L/R that can be transposed by SB transposase. Gateway cassette was combined to the pSB vectors to facilitate the cloning. Vectors with various tags, Flag, Myc, HA, V5 and SFB, were generated for multiple options. Moreover, we incorporated the CRISPR-Cas9 cassette into the pSB plasmids for gene knockout. Indeed, using one of these vectors (pSB-SFB-GFP), we performed Tandem Affinity Purification and identified that NFATc1 is a novel binding partner of FBW7. We also knocked out RCC2 and BRD7 using pSB-CRISPR vector respectively, and revealed the novel roles of these two proteins in mitosis. Conclusion: Our study demonstrated that the pSB series vectors are convenient and powerful tools for gene overexpression and knockout in mammalian cells, providing a new alternative approach for molecular cell biology research.

8.
Biochem Biophys Res Commun ; 497(2): 473-479, 2018 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-29408378

RESUMO

FBW7 is an E3 ubiquitin ligase and frequently mutated in various types of cancer. As a component of SCF ubiquitin ligase complex, FBW7 usually targets the substrates via K11 or K48-linked ubiquitylation and subsequent degradation of target proteins. Nevertheless, the role of FBW7 in mediating non-degradable ubiquitin signaling remains unknown in human cancers. In this study, we identified γ-catenin as a new binding protein of FBW7 by TAP-MS (tandem affinity purification-mass spectrum). Knockdown of FBW7 did not affect the stability of γ-catenin, but significantly reduced the K63-linked ubiquitin of γ-catenin, resulting in decreased expression of γ-catenin downstream gene 14-3-3σ. Rescue experiment revealed that γ-catenin promoted the expression of 14-3-3σ in a K63-linked ubiquitin signaling dependent manner. Furthermore, we showed that FBW7 cooperated with γ-catenin to inhibit G2/M cell cycle transition and cell proliferation. Taken together, our study uncovered a novel mechanism that FBW7 associated with γ-catenin and promoted its K63-linked ubiquitylation, providing new insights in understanding the role of FBW7 in inhibiting G2/M cell cycle transition and tumor cell proliferation.


Assuntos
Proliferação de Células , Proteína 7 com Repetições F-Box-WD/metabolismo , Ubiquitina/metabolismo , Ubiquitinação , gama Catenina/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular , Células HeLa , Humanos , Pontos de Checagem da Fase M do Ciclo Celular
9.
Di Yi Jun Yi Da Xue Xue Bao ; 25(8): 1060-1, 2005 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-16109578

RESUMO

OBJECTIVE: To investigate the effect of etomidate on the hemodynamics in elderly and shock patients during general anesthesia induction. METHODS: Totally 100 elderly patients or patients with hemorrhagic shock (ASA II -III ) undergoing surgery were studied. Anesthesia was induced with 4 microg/kg of fentanyl, 0.1 mg/kg of vecuronium and 0.2-0.3 mg/kg of etomidate, and the mean arterial blood pressure (MAP), heart rate (HR), stroke volume (SV), stroke index (SI), cardiac output (CO), cardiac index (CI), cardiac acceleration index (ACI), left cardiac work (LCW), and left cardiac work index (LCWI) were recorded using thoracic electrical bioimpedance (TEB) hemodynamic monitoring system before induction and at 1, 2 and 3 min after etomidate injection as well as at 3 min after intubation. RESULTS: After etomidate injection, MAP, HR, SV, SI, CO, CI, ACI, LCW and LCWI were decreased significantly as compared with those before induction (P<0.05). MAP, HR, CO, CI and ACI at 3 min after intubation were higher than those before induction (P<0.05), and the other indices resumed the baseline level. The amplitudes of such changes in the recorded indices was below 20% of the baseline level in the course of anesthesia induction. CONCLUSION: Cardiovascular hemodynamics may vary slightly during the course of induction with etomidate, which is an ideal drug for anesthesia induction for elderly or shock patients with unstable hemodynamics.


Assuntos
Anestesia Geral , Circulação Sanguínea/efeitos dos fármacos , Etomidato , Choque Hemorrágico/cirurgia , Abdome/cirurgia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Choque Hemorrágico/fisiopatologia
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