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1.
EBioMedicine ; 71: 103558, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34521054

RESUMO

BACKGROUND: Resistance to platinum-based chemotherapy is a major cause of therapeutic failure during the treatment of epithelial ovarian cancer (EOC) patients. Our study aims to elucidate the molecular mechanisms by which ZNF711 down regulation promotes CISPLATIN resistance in EOC. METHODS: ZNF711 expression in 150 EOC specimens was examined using immunohistochemistry. ZNF711 expression and the survival of EOC patients were assessed with a Kaplan-Meier analysis. The effects of ZNF711 expression on CDDP resistance were studied by IC50, Annexin V, and colony formation in vitro, and in an in vivo intra-peritoneal tumor model. The molecular mechanism was determined using a luciferase reporter assay, ChIP assay, CAPTURE approach, and co-IP assay. FINDINGS: ZNF711 down-regulation exerts a great impact on CDDP resistance for EOC patients by suppressing SLC31A1 and inhibiting CDDP influx. ZNF711 down-regulation promoted, while ZNF711 overexpression drastically inhibited CDDP resistance, both in vivo and in vitro. Mechanistically, the histone demethylase JHDM2A was recruited to the SLC31A1 promoter by ZNF711 and decreased the H3K9me2 level, resulting in the activation of SLC31A1 transcription and enhancement of CDDP uptake. Importantly, co-treatment with the histone methylation inhibitor, BIX-01294, increased the therapeutic efficacy of CDDP treatment in ZNF711-suppressed EOC cells. INTERPRETATION: These findings both verified the clinical importance of ZNF711 in CDDP resistance and provide novel therapeutic regimens for EOC treatment. FUNDING: This work was supported by the Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities; and China Postdoctoral Science Foundation.

2.
Mol Cancer ; 20(1): 98, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34325714

RESUMO

BACKGROUND: Breast cancer (BC) has a marked tendency to spread to the bone, resulting in significant skeletal complications and mortality. Recently, circular RNAs (circRNAs) have been reported to contribute to cancer initiation and progression. However, the function and mechanism of circRNAs in BC bone metastasis (BC-BM) remain largely unknown. METHODS: Bone-metastatic circRNAs were screened using circRNAs deep sequencing and validated using in situ hybridization in BC tissues with or without bone metastasis. The role of circIKBKB in inducing bone pre-metastatic niche formation and bone metastasis was determined using osteoclastogenesis, immunofluorescence and bone resorption pit assays. The mechanism underlying circIKBKB-mediated activation of NF-κB/bone remodeling factors signaling and EIF4A3-induced circIKBKB were investigated using RNA pull-down, luciferase reporter, chromatin isolation by RNA purification and enzyme-linked immunosorbent assays. RESULTS: We identified that a novel circRNA, circIKBKB, was upregulated significantly in bone-metastatic BC tissues. Overexpressing circIKBKB enhanced the capability of BC cells to induce formation of bone pre-metastatic niche dramatically by promoting osteoclastogenesis in vivo and in vitro. Mechanically, circIKBKB activated NF-κB pathway via promoting IKKß-mediated IκBα phosphorylation, inhibiting IκBα feedback loop and facilitating NF-κB to the promoters of multiple bone remodeling factors. Moreover, EIF4A3, acted acting as a pre-mRNA splicing factor, promoted cyclization of circIKBKB by directly binding to the circIKBKB flanking region. Importantly, treatment with inhibitor eIF4A3-IN-2 reduced circIKBKB expression and inhibited breast cancer bone metastasis effectively. CONCLUSION: We revealed a plausible mechanism for circIKBKB-mediated NF-κB hyperactivation in bone-metastatic BC, which might represent a potential strategy to treat breast cancer bone metastasis.

3.
Cancer Res ; 81(14): 3835-3848, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34049973

RESUMO

Mitochondrial dynamics play vital roles in the tumorigenicity and malignancy of various types of cancers by promoting the tumor-initiating potential of cancer cells, suggesting that targeting crucial factors that drive mitochondrial dynamics may lead to promising anticancer therapies. In the current study, we report that overexpression of mitochondrial fission factor (MFF), which is upregulated significantly in liver cancer-initiating cells (LCIC), promotes mitochondrial fission and enhances stemness and tumor-initiating capability in non-LCICs. MFF-induced mitochondrial fission evoked mitophagy and asymmetric stem cell division and promoted a metabolic shift from oxidative phosphorylation to glycolysis that decreased mitochondrial reactive oxygen species (ROS) production, which prevented ROS-mediated degradation of the pluripotency transcription factor OCT4. CRISPR affinity purification in situ of regulatory elements showed that T-box transcription factor 19 (TBX19), which is overexpressed uniquely in LCICs compared with non-LCICs and liver progenitor cells, forms a complex with PRMT1 on the MFF promoter in LCICs, eliciting epigenetic histone H4R3me2a/H3K9ac-mediated transactivation of MFF. Targeting PRMT1 using furamidine, a selective pharmacologic inhibitor, suppressed TBX19-induced mitochondrial fission, leading to a profound loss of self-renewal potential and tumor-initiating capacity of LCICs. These findings unveil a novel mechanism underlying mitochondrial fission-mediated cancer stemness and suggest that regulation of mitochondrial fission via inhibition of PRMT1 may be an attractive therapeutic option for liver cancer treatment. SIGNIFICANCE: These findings show that TBX19/PRMT1 complex-mediated upregulation of MFF promotes mitochondrial fission and tumor-initiating capacity in liver cancer cells, identifying PRMT1 as a viable therapeutic target in liver cancer.

4.
Cancer Res ; 81(13): 3525-3538, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33975879

RESUMO

Balancing mRNA nuclear export kinetics with its nuclear decay is critical for mRNA homeostasis control. How this equilibrium is aberrantly disrupted in esophageal cancer to acquire cancer stem cell properties remains unclear. Here we find that the RNA-binding protein interleukin enhancer binding factor 2 (ILF2) is robustly upregulated by nicotine, a major chemical component of tobacco smoke, via activation of JAK2/STAT3 signaling and significantly correlates with poor prognosis in heavy-smoking patients with esophageal cancer. ILF2 bound the THO complex protein THOC4 as a regulatory cofactor to induce selective interactions with pluripotency transcription factor mRNAs to promote their assembly into export-competent messenger ribonucleoprotein complexes. ILF2 facilitated nuclear mRNA export and inhibited hMTR4-mediated exosomal degradation to promote stabilization and expression of SOX2, NANOG, and SALL4, resulting in enhanced stemness and tumor-initiating capacity of esophageal cancer cells. Importantly, inducible depletion of ILF2 significantly increased the therapeutic efficiency of cisplatin and abrogated nicotine-induced chemoresistance in vitro and in vivo. These findings reveal a novel role of ILF2 in nuclear mRNA export and maintenance of cancer stem cells and open new avenues to overcome smoking-mediated chemoresistance in esophageal cancer. SIGNIFICANCE: This study defines a previously uncharacterized role of nicotine-regulated ILF2 in facilitating nuclear mRNA export to promote cancer stemness, suggesting a potential therapeutic strategy against nicotine-induced chemoresistance in esophageal cancer.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33821605

RESUMO

Efficient removal of uranium (U) from aqueous solutions is crucial for ecological safety. Functionalized magnetic nanoparticles provide a promising strategy for radionuclide recovery and separation. However, designing and synthesizing magnetic adsorbents with high sorption capacity and selectivity, accompanied by excellent stability and reusability, remain a challenge. In this work, novel amidoxime-functionalized flower-like magnetic Fe3O4@TiO2 core-shell microspheres are designed and synthesized to efficiently remove U(VI) from aqueous solutions and actual seawater. The magnetic Fe3O4 core facilitates easy separation by an external magnetic field, and flower-like TiO2 nanosheets provide abundant specific surface areas and functionalization sites. The grafted amidoxime (AO) groups could function as a claw for catching uranium. The maximum adsorption capacity on U(VI) of the designed nanospheres reaches 313.6 mg·g-1 at pH 6.0, and the adsorption efficiency is maintained at 97% after 10 cycles. In addition, the excellent selectivity of the magnetic recyclable AO-functioning Fe3O4@TiO2 microspheres endows the potential of uranium extraction from seawater. The designed material provides an effective and applicable diagram for radioactive element elimination and enrichment.

6.
Cancer Lett ; 503: 43-53, 2021 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-33352248

RESUMO

Chemotherapy regimens containing cisplatin remain the first-line treatments for patients with oral squamous cell cancer (OSCC); however, the treatment effect is often transient because of chemoresistance and recurrence. Understanding the mechanisms of chemoresistance in OSCC might provide novel targetable vulnerabilities. In the present study, we revealed that Forkhead box D1 (FOXD1) is upregulated in OSCC and predicted poor prognosis. Moreover, ectopic expression of FOXD1 promoted, while silencing of FOXD1 inhibited, the epithelial-mesenchymal transition (EMT) and chemoresistance of OSCC, both in vitro and in vivo. Mechanistically, FOXD1 binds to the promoter of long non-coding RNA Cytoskeleton Regulator RNA (CYTOR) and activates its transcription. CYTOR then acts as a competing endogenous RNA to inhibit miR-1252-5p and miR-3148, thus upregulating lipoma preferred partner (LPP) expression. Importantly, the CYTOR/LPP axis was proven to be essential for FOXD1-induced EMT and chemoresistance in OSCC. These findings reveal a novel mechanism for the chemotherapy resistance of OSCC, suggesting that FOXD1 might be a potential prognostic marker and anti-resistance therapeutic target.


Assuntos
Carcinoma de Células Escamosas/patologia , Resistencia a Medicamentos Antineoplásicos , Fatores de Transcrição Forkhead/metabolismo , Neoplasias Bucais/patologia , RNA Longo não Codificante/genética , Regulação para Cima , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Proteínas do Citoesqueleto/genética , Transição Epitelial-Mesenquimal , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas com Domínio LIM/genética , Camundongos , MicroRNAs/genética , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Transplante de Neoplasias , Prognóstico , Regiões Promotoras Genéticas
7.
Cell Death Dis ; 11(1): 41, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959918

RESUMO

Laryngeal squamous cell carcinoma (LSCC) is a common head and neck cancer. Despite recently improved management of LSCC, chemotherapy resistance of patients remains a challenge. In this study, we identified that long noncoding RNA FOXD2-AS1 regulates LSCC therapeutic resistance by augmenting LSCC stemness. LSCC chemotherapy-resistant patients showed increased FOXD2-AS1 expression compared with that in chemotherapy-sensitive patients, which predicted poor prognosis. Gain- or loss-of-function experiments showed that upregulated FOXD2-AS1 maintained cancer stemness, reducing the response to chemotherapy, while FOXD2-AS1 downregulation had the opposite effects. FOXD2-AS1 acted as a scaffold for STAT3 and PRMT5, promoting STAT3 transcriptional activity, which is essential to maintain cancer stemness and promote chemotherapeutic resistance. Interfering with FOXD2-AS1 using short hairpin RNA rescued LSCC's chemotherapeutic sensitivity. Thus, FOXD2-AS1 promotes LSCC chemotherapeutic resistance and is an upstream activator of STAT3, making FOXD2-AS1 a potential therapeutic target to improve the chemotherapy effect in LSCC patients.


Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Laríngeas/genética , RNA Longo não Codificante/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Prognóstico , Ligação Proteica/efeitos dos fármacos , Proteína-Arginina N-Metiltransferases/metabolismo , RNA Longo não Codificante/genética , Transcrição Genética/efeitos dos fármacos , Regulação para Cima/genética
8.
Nat Commun ; 10(1): 3761, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434880

RESUMO

The mechanisms underlying how cells subjected to genotoxic stress reestablish reduction-oxidation (redox) homeostasis to scavenge genotoxic stress-induced reactive oxygen species (ROS), which maintains the physiological function of cellular processes and cell survival, remain unclear. Herein, we report that, via a TCF-independent mechanism, genotoxic stress induces the enrichment of ß-catenin in chromatin, where it forms a complex with ATM phosphorylated-JDP2 and PRMT5. This elicits histone H3R2me1/H3R2me2s-induced transcriptional activation by the recruitment of the WDR5/MLL methyltransferase complexes and concomitant H3K4 methylation at the promoters of multiple genes in GSH-metabolic cascade. Treatment with OICR-9429, a small-molecule antagonist of the WDR5-MLL interaction, inhibits the ß-catenin/JDP2/PRMT5 complex-reestablished GSH metabolism, leading to a lethal increase in the already-elevated levels of ROS in the genotoxic-agent treated cancer cells. Therefore, our results unveil a plausible role for ß-catenin in reestablishing redox homeostasis upon genotoxic stress and shed light on the mechanisms of inducible chemotherapy resistance in cancer.


Assuntos
Dano ao DNA/fisiologia , Glutationa/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/metabolismo , beta Catenina/metabolismo , Células A549 , Animais , Compostos de Bifenilo/farmacologia , Linhagem Celular Tumoral , Cromatina , Di-Hidropiridinas/farmacologia , Feminino , Glutationa/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Homeostase , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteína de Leucina Linfoide-Mieloide/metabolismo , Neoplasias/metabolismo , Regiões Promotoras Genéticas , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Ativação Transcricional
9.
Clin Cancer Res ; 25(3): 1022-1035, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30279231

RESUMO

PURPOSE: The development of resistance to platinum-based chemotherapy remains the unsurmountable obstacle in cancer treatment and consequently leads to tumor relapse. This study aims to investigate the mechanism by which loss of RBMS3 induced chemoresistance in epithelial ovarian cancer (EOC). EXPERIMENTAL DESIGN: FISH and IHC were used to determine deletion frequency and expression of RBMS3 in 15 clinical EOC tissues and 150 clinicopathologically characterized EOC specimens. The effects of RBMS3 deletion and CBP/ß-catenin antagonist PRI-724 in chemoresistance were examined by clone formation and Annexin V assays in vitro, and by intraperitoneal tumor model in vivo. The mechanism by which RBMS3 loss sustained activation of miR-126-5p/ß-catenin/CBP signaling and the effects of RBMS3 and miR-126-5p competitively regulating DKK3, AXIN1, BACH1, and NFAT5 was explored using CLIP-seq, RIP, electrophoretic mobility shift, and immunoblotting and immunofluorescence assays. RESULTS: Loss of RBMS3 in EOC was correlated with the overall and relapse-free survival. Genetic ablation of RBMS3 significantly enhanced, whereas restoration of RBMS3 reduced, the chemoresistance ability of EOC cells both in vitro and in vivo. RBMS3 inhibited ß-catenin/CBP signaling through directly associating with and stabilizing multiple negative regulators, including DKK3, AXIN1, BACH1, and NFAT5, via competitively preventing the miR-126-5p-mediated repression of these transcripts. Importantly, cotherapy of CBP/ß-catenin antagonist PRI-724 induced sensitization of RBMS3-deleted EOC to platinum therapy. CONCLUSIONS: Our results demonstrate that genetic ablation of RBMS3 contributes to chemoresistance and PRI-724 may serve as a potential tailored treatment for patients with RBMS3-deleted EOC.


Assuntos
Carcinoma Epitelial do Ovário/genética , Resistencia a Medicamentos Antineoplásicos/genética , Deleção de Genes , MicroRNAs/genética , Fragmentos de Peptídeos/genética , Proteínas de Ligação a RNA/genética , Sialoglicoproteínas/genética , Transativadores/genética , beta Catenina/genética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/patologia , Cisplatino/administração & dosagem , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Pirimidinonas/administração & dosagem , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transativadores/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Cancer Res ; 78(22): 6399-6412, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30254148

RESUMO

Blocking genotoxic stress-induced NF-κB activation would substantially enhance the anticancer efficiency of genotoxic chemotherapy. Unlike the well-established classical NF-κB pathway, the genotoxic agents-induced "nuclear-to-cytoplasmic" NF-κB pathway is initiated from the nucleus and transferred to the cytoplasm. However, the mechanism linking nuclear DNA damage signaling to cytoplasmic IKK activation remains unclear. Here, we report that TRIM37, a novel E3 ligase, plays a vital role in genotoxic activation of NF-κB via monoubiquitination of NEMO at K309 in the nucleus, consequently resulting in nuclear export of NEMO and IKK/NF-κB activation. Clinically, TRIM37 levels correlated positively with levels of activated NF-κB and expression of Bcl-xl and XIAP in esophageal cancer specimens, which also associated positively with clinical stage and tumor-node-metastasis classification and associated inversely with overall and relapse-free survival in patients with esophageal cancer. Overexpression of TRIM37 conferred resistance to the DNA-damaging anticancer drug cisplatin in vitro and in vivo through activation of the NF-κB pathway. Genotoxic stress-activated ATM kinase directly interacted with and phosphorylated TRIM37 in the cytoplasm, which induced translocation of TRIM37 into the nucleus, where it formed a complex with NEMO and TRAF6 via a TRAF6-binding motif (TBM). Importantly, blocking the ATM/TRIM37/NEMO axis via cell-penetrating TAT-TBM peptide abrogated genotoxic agent-induced NEMO monoubiquitination and NF-κB activity, resulting in hypersensitivity of cancer cells to genotoxic drugs. Collectively, our results unveil a pivotal role for TRIM37 in genotoxic stress and shed light on mechanisms of inducible chemotherapy resistance in cancer.Significance: In response to genotoxic stress, TRIM37 activates NF-κB signaling via monoubiquitination of NEMO, which subsequently promotes cisplatin chemoresistance and tumor relapse in cancer. Cancer Res; 78(22); 6399-412. ©2018 AACR.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Quinase I-kappa B/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Proteínas Nucleares/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular , Metástase Linfática , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Mutagênicos , Transplante de Neoplasias , Fosforilação , Transdução de Sinais , Processos Estocásticos , Fator 6 Associado a Receptor de TNF/metabolismo , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases
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