RESUMEN
Metastasis is a major cause of cancer therapy failure and mortality. However, targeting metastatic seeding and colonization remains a significant challenge. In this study, we identified NSD2, a histone methyltransferase responsible for dimethylating histone 3 at lysine 36, as being overexpressed in metastatic tumors. Our findings suggest that NSD2 overexpression enhances tumor metastasis both in vitro and in vivo. Further analysis revealed that NSD2 promotes tumor metastasis by activating Rac1 signaling. Mechanistically, NSD2 combines with and activates Tiam1 (T lymphoma invasion and metastasis 1) and promotes Rac1 signaling by methylating Tiam1 at K724. In vivo and in vitro studies revealed that Tiam1 K724 methylation could be a predictive factor for cancer prognosis and a potential target for metastasis inhibition. Furthermore, we have developed inhibitory peptide which was proved to inhibit tumor metastasis through blocking the interaction between NSD2 and Tiam1. Our results demonstrate that NSD2-methylated Tiam1 promotes Rac1 signaling and cancer metastasis. These results provide insights into the inhibition of tumor metastasis.
Asunto(s)
Neoplasias del Colon , Factores de Intercambio de Guanina Nucleótido , Humanos , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Transducción de Señal/fisiología , Invasividad Neoplásica/patología , Metilación , Proteína de Unión al GTP rac1/genética , Proteína de Unión al GTP rac1/metabolismoRESUMEN
Extracellular cytokines are enriched in the tumor microenvironment and regulate various important properties of cancers, including autophagy. However, the precise molecular mechanisms underlying the link between autophagy and extracellular cytokines remain to be elucidated. In the present study, we demonstrate that IL-6 activates autophagy through the IL-6/JAK2/BECN1 pathway and promotes chemotherapy resistance in colorectal cancer (CRC). Mechanistically, IL-6 triggers the interaction between JAK2 and BECN1, where JAK2 phosphorylates BECN1 at Y333. We demonstrate that BECN1 Y333 phosphorylation is crucial for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation. Furthermore, we investigate BECN1 Y333 phosphorylation as a predictive marker for poor CRC prognosis and chemotherapy resistance. Combination treatment with autophagy inhibitors or pharmacological agents targeting the IL-6/JAK2/BECN1 signaling pathway may represent a potential strategy for CRC cancer therapy.
Asunto(s)
Autofagia/fisiología , Beclina-1/metabolismo , Quimioterapia , Interleucina-6/metabolismo , Autofagia/efectos de los fármacos , Proteínas Relacionadas con la Autofagia/metabolismo , Beclina-1/química , Beclina-1/genética , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Interleucina-6/farmacología , Janus Quinasa 2/química , Janus Quinasa 2/metabolismo , Fosforilación , Dominios y Motivos de Interacción de Proteínas , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
A Correction to this paper has been published: https://doi.org/10.1038/s41556-021-00686-x.
RESUMEN
Tumor angiogenesis plays vital roles in tumorigenesis and development; regulatory mechanism of angiogenesis is still not been fully elucidated. NSD2, a histone methyltransferase catalyzing di-methylation of histone H3 at lysine 36, has been proved a critical molecule in proliferation, metastasis, and tumorigenesis. But its role in tumor angiogenesis remains unknown. Here we demonstrated that NSD2 promoted tumor angiogenesis in vitro and in vivo. Furthermore, we confirmed that the angiogenic function of NSD2 was mediated by STAT3. Momentously, we found that NSD2 promoted the methylation and activation of STAT3. In addition, mass spectrometry and site-directed mutagenesis assays revealed that NSD2 methylated STAT3 at lysine 163 (K163). Meanwhile, K to R mutant at K163 of STAT3 attenuated the activation and angiogenic function of STAT3. Taken together, we conclude that methylation of STAT3 catalyzed by NSD2 promotes the activation of STAT3 pathway and enhances the ability of tumor angiogenesis. Our findings investigate a NSD2-dependent methylation-phosphorylation regulation pattern of STAT3 and reveal that NSD2/STAT3/VEGFA axis might be a potential target for tumor therapy.
Asunto(s)
Neoplasias del Colon/irrigación sanguínea , N-Metiltransferasa de Histona-Lisina/metabolismo , Proteínas Represoras/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Carcinogénesis , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Xenoinjertos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Metilación , Ratones , Ratones Desnudos , Neovascularización Patológica/metabolismoRESUMEN
The histone methyltransferase SETDB1 catalyzes the addition of methyl groups to histone H3 at lysine 9, and upregulation of SETDB1 is associated with poor prognosis in cancer patients. Here, we describe how overexpression of SETDB1 contributes to colorectal cancer (CRC) tumorigenesis and drug resistance. We show that SETDB1 is upregulated in CRC, and its level correlates with poor clinical outcome. SETDB1 attenuation inhibits CRC cell proliferation Mechanistically, SETDB1 promotes cell proliferation by upregulating Akt activation. Further, SETDB1 is essential for the tumorigenic activity of Akt. Functional characterization revealed that inhibition of SETDB1 reduces cell growth in CRC resistant to targeted treatments in vitro and in vivo, KRAS-mutated CRC included. Taken together, our results indicate that SETDB1 is a major driver of CRC and may serve as a potential target for the treatment of KRAS-mutated CRC.
Asunto(s)
Carcinogénesis/efectos de los fármacos , Cetuximab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , N-Metiltransferasa de Histona-Lisina/genética , Anciano , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histona Metiltransferasas/genética , Histonas/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Histone lysine demethylase 4B (KDM4B) has been implicated in various pathological processes and human diseases. Glucose metabolism is the main pattern of energy supply in cells and its dysfunction is closely related to tumorigenesis. Recent study shows that KDM4B protects against obesity and metabolic dysfunction. We realized the significant role of KDM4B in metabolism. However, the role of KDM4B in glucose metabolism remains unclear. Here, we sought to delineate the role and mechanism of KDM4B in glucose metabolism in colorectal cancer (CRC). METHODS: We first analyzed the role of KDM4B in glucose uptake and CRC growth. We then investigated the consequences of KDM4B inhibition on the expression of GLUT1 and AKT signaling, also explored the underlying mechanism. Finally, we detected the mechanism in vivo and assessed the potential correlation between the expression of KDM4B and CRC prognosis. RESULTS: We found that KDM4B promoted glucose uptake and ATP production by regulating the expression of GLUT1 via the AKT signaling pathway. KDM4B could interact with TRAF6 and promote TRAF6-mediated ubiquitination of AKT for AKT activation. Furthermore, we demonstrated that KDM4B was overexpressed in CRC specimens and high level of KDM4B was associated with a poor survival rate in CRC patients. CONCLUSIONS: These findings reveal that KDM4B plays an important role in promoting CRC progression by enhancing glucose metabolism.
Asunto(s)
Neoplasias Colorrectales/patología , Transportador de Glucosa de Tipo 1/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Histona Demetilasas con Dominio de Jumonji/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Regulación hacia Arriba , Adenosina Trifosfato/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Femenino , Glucosa/metabolismo , Células HCT116 , Humanos , Histona Demetilasas con Dominio de Jumonji/genética , Masculino , Ratones , Trasplante de Neoplasias , Pronóstico , Análisis de Supervivencia , UbiquitinaciónRESUMEN
Angiogenesis plays important roles in solid tumors progression. Growth factors such as vascular endothelial growth factors (VEGFs) can induce angiogenesis and hypoxia promotes the expression of VEGFs through activating hypoxia-inducible factor 1 (HIF-1α). However, the regulation of HIF-1α still not been fully understood. Here, we demonstrate that the Sine Oculis Homeobox Homolog 4 (SIX4) is up-regulated in colorectal cancer (CRC) and high expression of SIX4 predicts a poor prognosis. Overexpression of SIX4 enhances tumor growth and angiogenesis in vitro and in vivo, while knockdown of SIX4 inhibits tumor growth and angiogenesis. Furthermore, we show that SIX4 increases the expression of VEGF-A by coordinating with the HIF-1α. Mechanically, we explore that SIX4 up-regulates the expression of HIF-1α depending on Akt activation. Collectively, we demonstrate that SIX4 is functional in regulating tumor angiogenesis and SIX4 might be used as anti-angiogenic therapy in CRC.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/irrigación sanguínea , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Neovascularización Patológica/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transactivadores/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Femenino , Proteínas de Homeodominio/genética , Humanos , Metástasis Linfática , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Neovascularización Patológica/metabolismo , Pronóstico , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal , Tasa de Supervivencia , Transactivadores/genética , Células Tumorales Cultivadas , Cicatrización de Heridas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The serine/threonine kinase Akt plays a central role in cell proliferation, survival and metabolism, and its hyperactivation is linked to cancer progression. Here we report that Akt undergoes K64 methylation by SETDB1, which is crucial for cell membrane recruitment, phosphorylation and activation of Akt following growth factor stimulation. Furthermore, we reveal an adaptor function of histone demethylase JMJD2A, which is important for recognizing Akt K64 methylation and recruits E3 ligase TRAF6 and Skp2-SCF to the Akt complex, independently of its demethylase activity, thereby initiating K63-linked ubiquitination, cell membrane recruitment and activation of Akt. Notably, the cancer-associated Akt mutant E17K displays enhanced K64 methylation, leading to its hyper-phosphorylation and activation. SETDB1-mediated Akt K64 methylation is upregulated and correlated with Akt hyperactivation in non-small-cell lung carcinoma (NSCLC), promotes tumour development and predicts poor outcome. Collectively, these findings reveal complicated layers of Akt activation regulation coordinated by SETDB1-mediated Akt K64 methylation to drive tumorigenesis.
Asunto(s)
Carcinogénesis/metabolismo , Proteína Metiltransferasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ubiquitinación , Células A549 , Animales , Carcinogénesis/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Femenino , Células HEK293 , N-Metiltransferasa de Histona-Lisina , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Lisina/genética , Lisina/metabolismo , Metilación , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Desnudos , Células 3T3 NIH , Proteína Metiltransferasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Trasplante HeterólogoRESUMEN
Clinical and experimental evidence has shown that tumor-associated macrophages promote cancer initiation and progression. However, the macrophage-derived molecular determinants that regulate colorectal cancer metastasis have not been fully characterized. Here, we demonstrate that M2 macrophage-regulated colorectal cancer cells' migration and invasion is dependent upon M2 macrophage-derived exosomes (MDE). MDE displayed a high expression level of miR-21-5p and miR-155-5p, and MDE-mediated colorectal cancer cells' migration and invasion depended on these two miRNAs. Mechanistically, miR-21-5p and miR-155-5p were transferred to colorectal cancer cells by MDE and bound to the BRG1 coding sequence, downregulating expression of BRG1, which has been identified as a key factor promoting the colorectal cancer metastasis, yet is downregulated in metastatic colorectal cancer cells. Collectively, these findings show that M2 macrophages induce colorectal cancer cells' migration and invasion and provide significant plasticity of BRG1 expression in response to tumor microenvironments during malignant progression. This dynamic and reciprocal cross-talk between colorectal cancer cells and M2 macrophages provides a new opportunity for the treatment of metastatic colorectal cancer. SIGNIFICANCE: These findings report a functional role for miRNA-containing exosomes derived from M2 macrophages in regulating migration and invasion of colorectal cancer cells.
Asunto(s)
Neoplasias Colorrectales/patología , ADN Helicasas/metabolismo , Exosomas/metabolismo , Neoplasias Pulmonares/secundario , Macrófagos/patología , MicroARNs/genética , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , ADN Helicasas/genética , Exosomas/genética , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Metástasis de la Neoplasia , Proteínas Nucleares/genética , Pronóstico , Tasa de Supervivencia , Factores de Transcripción/genética , Células Tumorales Cultivadas , Microambiente Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by the persistent deposition of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Brg1, the core subunit of the SWI/SNF chromatin remodeling complex, has been proved to associated with nonalcoholic steatohepatitis which may progress to cirrhosis. Herein, we determined whether Brg1 regulates liver fibrosis and examined its mechanism by focusing on HSCs activation. In this study, we demonstrate that Brg1 is elevated in human and mouse fibrotic liver tissues and Brg1 mediate the profibrotic response in activated HSCs. Our data indicate that Brg1 regulates the activation of HSCs through TGFß/Smad signal pathway. Moreover, Brg1 deficiency mice displayed decreased HSCs activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. In addition, Brg1 expression is positively correlated with liver fibrosis in cirrhotic patients and may be a prognostic factor in HCC. Collectively, we demonstrate that Brg1 promotes liver fibrosis by activating HSCs and may represent a potential target for anti-fibrotic therapies.
Asunto(s)
ADN Helicasas/metabolismo , Células Estrelladas Hepáticas/metabolismo , Cirrosis Hepática/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Células Cultivadas , ADN Helicasas/genética , Células Estrelladas Hepáticas/citología , Humanos , Cirrosis Hepática/patología , Proteínas Nucleares/genética , Factores de Transcripción/genéticaRESUMEN
Angiogenesis plays an important role in tumor growth and progression in solid tumors. Vascular endothelial growth factor (VEGF) is one of the most critical and specific factors that stimulate both physiological and pathological angiogenesis. Here, we report a novel role of BRG1, the core subunit of SWI/SNF family complexes, in angiogenesis. In this study, we demonstrate that BRG1 is overexpressed in colorectal cancer and decreased expression of BRG1 not only blocks cell proliferation but remarkably inhibits the ability of HUVECs to form capillary-like structures. Moreover, our study shows that BRG1 can regulate the expression of VEGF-A by interacting with HIF-1α. Furthermore, we find VEGF-A is overexpressed in colorectal cancer and is positively correlated with BRG1 expression. Taken together, our study demonstrated that BRG1 can promote VEGF-A expression and angiogenesis in colorectal cancer and BRG1 may be a novel drug target for the treatment of colorectal cancer.
Asunto(s)
Neoplasias Colorrectales/irrigación sanguínea , Neoplasias Colorrectales/genética , ADN Helicasas/fisiología , Neovascularización Patológica/genética , Proteínas Nucleares/fisiología , Factores de Transcripción/fisiología , Factor A de Crecimiento Endotelial Vascular/genética , Animales , Línea Celular Tumoral , Células Cultivadas , Neoplasias Colorrectales/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Ratones DesnudosRESUMEN
Tumor lymphangiogenesis is an important early event in tumorigenesis, one that promotes lymphatic metastasis. BRG1 (also known as SMARCA4) is a central component of the SWI/SNF chromatin-remodeling complex. In a previous work, we have reported that decreased BRG1 could promote colon cancer cell migration and invasion, and that the BRG1 expression level is negatively correlated with lymphatic metastasis. In the current study, we provide a comprehensive analysis of the role of BRG1 during lymphangiogenesis in colorectal cancer. Lymphatic vessels are more abundant in BRG1 low-expression tumors than in BRG1 high-expression tumors. We investigate the process by which BRG1 can promote VEGFC transcription and induce lymphangiogenesis in vivo and in vitro. We show that BRG1 controls lymphangiogenesis by binding to STAT3 and regulating STAT3 activation. We also prove the mechanisms through clinical samples. In summary, our demonstration of the important roles of the BRG1/STAT3/VEGFC in tumor-associated lymphangiogenesis might lead to the discovery of novel therapeutic targets in the treatment of cancers with BRG1 loss of function.