RESUMEN
Platinum-based neoadjuvant therapy represented by cisplatin is widely employed in treating Triple-Negative Breast Cancer (TNBC), a particularly aggressive subtype of breast cancer. Nevertheless, the emergence of cisplatin resistance presents a formidable challenge to clinical chemotherapy efficacy. Herein, we revealed the critical role of tumor microenvironment (TME) derived exosomal miR-3960 and phosphorylation at the S16 site of PIMREG in activating NF-κB signaling pathway and promoting cisplatin resistance of TNBC. Detailed regulatory mechanisms revealed that SOD1-upregulated fibroblasts secrete miR-3960 and are then transported into TNBC cells via exosomes. Within TNBC cells, miR-3960 targets and inhibits the expression of BRSK2, an AMPK protein kinase family member. Furthermore, we emphasized that BRSK2 contributes to ubiquitination degradation of PIMREG and modulates subsequent activation of the NF-κB signaling pathway by mediating PIMREG phosphorylation at the S16 site, ultimately affects the cisplatin resistance of TNBC. In conclusion, our research demonstrated the crucial role of SOD1high fibroblast, exosomal miR-3960 and S16 site phosphorylated PIMREG in regulating the NF-κB signaling pathway and cisplatin resistance of TNBC. These findings provided significant potential as biomarkers for accurately diagnosing cisplatin-resistant TNBC patients and guiding chemotherapy strategy selection.
Asunto(s)
Cisplatino , Resistencia a Antineoplásicos , Exosomas , MicroARNs , Neoplasias de la Mama Triple Negativas , Animales , Femenino , Humanos , Ratones , Antineoplásicos/farmacología , Línea Celular Tumoral , Cisplatino/farmacología , Exosomas/metabolismo , Exosomas/genética , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , MicroARNs/genética , MicroARNs/metabolismo , FN-kappa B/metabolismo , FN-kappa B/genética , Fosforilación , Transducción de Señal/efectos de los fármacos , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Microambiente TumoralRESUMEN
Deubiquitinating enzymes (DUBs) are promising targets for cancer therapy because of their pivotal roles in various physiological and pathological processes. Among these, ubiquitin-specific peptidase 26 (USP26) is a protease with crucial regulatory functions. Our study sheds light on the upregulation of USP26 in colorectal cancer (CRC), in which its increased expression correlates with an unfavorable prognosis. Herein, we evidenced the role of USP26 in promoting CRC tumorigenesis in a parkin RBR E3 ubiquitin-protein ligase (PRKN) protein-dependent manner. Our investigation revealed that USP26 directly interacted with PRKN protein, facilitating its deubiquitination, and subsequently reducing its activity. Additionally, we identified the K129 site on PRKN as a specific target for USP26-mediated deubiquitination. Our research highlights that a K-to-R mutation at the site on PRKN diminishes its potential for activation and ability to mediate mitophagy. In summary, our findings underscore the significance of USP26-mediated deubiquitination in restraining the activation of the PRKN-mediated mitophagy pathway, ultimately driving CRC tumorigenesis. This study not only elucidated the multifaceted role of USP26 in CRC but also introduced a promising avenue for therapeutic exploration through the development of small molecule inhibitors targeting USP26. This strategy holds promise as a novel therapeutic approach for CRC.
Asunto(s)
Carcinogénesis , Neoplasias Colorrectales , Mitofagia , Ubiquitina-Proteína Ligasas , Ubiquitinación , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Humanos , Mitofagia/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Ratones , Línea Celular Tumoral , Cisteína Endopeptidasas/metabolismo , Cisteína Endopeptidasas/genética , Ratones Desnudos , Regulación Neoplásica de la Expresión GénicaRESUMEN
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.