Tailoring a novel colorectal cancer stem cell-targeted therapy by inhibiting the SMYD3/c-MYC axis
Abstract Cancer stem cells (CSCs) are responsible for colorectal cancer (CRC) chemoresistance, recurrence, and metastasis. Therefore, identifying molecular stemness targets that are involved in tumor growth is crucial for effective treatment. Here, we performed an extensive in vitro and in vivo mole...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-06-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02290-z |
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| author | Martina Lepore Signorile Elisabetta Di Nicola Giovanna Forte Paola Sanese Candida Fasano Vittoria Disciglio Katia De Marco Marialaura Latrofa Loris De Cecco Marica Ficorilli Marta Lucchetta Erica Torchia Chiara Dossena Giusy Bianco Vito Spilotro Claudia Ferroni Nicoletta Labarile Raffaele Armentano Francesco Albano Anna Mestice Gianluigi Gigante Valerio Lantone Giuliano Lantone Leonardo Vincenti Alberto Del Rio Greta Varchi Valentina Grossi Cristiano Simone |
| author_facet | Martina Lepore Signorile Elisabetta Di Nicola Giovanna Forte Paola Sanese Candida Fasano Vittoria Disciglio Katia De Marco Marialaura Latrofa Loris De Cecco Marica Ficorilli Marta Lucchetta Erica Torchia Chiara Dossena Giusy Bianco Vito Spilotro Claudia Ferroni Nicoletta Labarile Raffaele Armentano Francesco Albano Anna Mestice Gianluigi Gigante Valerio Lantone Giuliano Lantone Leonardo Vincenti Alberto Del Rio Greta Varchi Valentina Grossi Cristiano Simone |
| author_sort | Martina Lepore Signorile |
| collection | DOAJ |
| description | Abstract Cancer stem cells (CSCs) are responsible for colorectal cancer (CRC) chemoresistance, recurrence, and metastasis. Therefore, identifying molecular stemness targets that are involved in tumor growth is crucial for effective treatment. Here, we performed an extensive in vitro and in vivo molecular and functional characterization, revealing the pivotal role of the lysine methyltransferase SET and MYND Domain Containing 3 (SMYD3) in colorectal cancer stem cell (CRC-SC) biology. Specifically, we showed that SMYD3 interacts with and methylates c-MYC at K158 and K163, thereby modulating its transcriptional activity, which is implicated in stemness and colorectal malignancy. Our in vitro data suggest that SMYD3 pharmacological inhibition or its stable genetic ablation affects the clonogenic and self-renewal potential of patient-derived CRC-SCs and organoids by altering their molecular signature. Moreover, we found that SMYD3 stable knock-out or pharmacological inhibition drastically reduces CRC tumorigenicity in vivo and CRC-SC metastatic potential. Overall, our findings identify SMYD3 as a promising therapeutic target acting directly on c-MYC, with potential implications for countering CRC-SC proliferation and metastatic dissemination. |
| format | Article |
| id | doaj-art-514cacfbb9a2428aa874176a3113bc3b |
| institution | DOAJ |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-514cacfbb9a2428aa874176a3113bc3b2025-08-20T03:04:21ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-06-0110112610.1038/s41392-025-02290-zTailoring a novel colorectal cancer stem cell-targeted therapy by inhibiting the SMYD3/c-MYC axisMartina Lepore Signorile0Elisabetta Di Nicola1Giovanna Forte2Paola Sanese3Candida Fasano4Vittoria Disciglio5Katia De Marco6Marialaura Latrofa7Loris De Cecco8Marica Ficorilli9Marta Lucchetta10Erica Torchia11Chiara Dossena12Giusy Bianco13Vito Spilotro14Claudia Ferroni15Nicoletta Labarile16Raffaele Armentano17Francesco Albano18Anna Mestice19Gianluigi Gigante20Valerio Lantone21Giuliano Lantone22Leonardo Vincenti23Alberto Del Rio24Greta Varchi25Valentina Grossi26Cristiano Simone27Medical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research HospitalMedical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research HospitalMedical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research HospitalMedical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research HospitalMedical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research HospitalMedical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research HospitalMedical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research HospitalMedical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research HospitalIntegrated Biology of Rare Tumors, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei TumoriIntegrated Biology of Rare Tumors, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei TumoriIntegrated Biology of Rare Tumors, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei TumoriIntegrated Biology of Rare Tumors, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei TumoriIntegrated Biology of Rare Tumors, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei TumoriAnimal facility, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research HospitalAnimal facility, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research HospitalInstitute for Organic Synthesis and Photoreactivity, National Research CouncilHistopathology Unit, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research HospitalHistopathology Unit, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research HospitalDepartment of Precision and Regenerative Medicine and Jonic Area (DiMePRe-J), University of Bari Aldo MoroDepartment of Precision and Regenerative Medicine and Jonic Area (DiMePRe-J), University of Bari Aldo MoroDepartment of Precision and Regenerative Medicine and Jonic Area (DiMePRe-J), University of Bari Aldo MoroDepartment of Precision and Regenerative Medicine and Jonic Area (DiMePRe-J), University of Bari Aldo MoroUnit of Surgery, “Lorenzo Bonomo” HospitalDepartment of General Surgery, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research HospitalInstitute for Organic Synthesis and Photoreactivity, National Research CouncilInstitute for Organic Synthesis and Photoreactivity, National Research CouncilMedical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research HospitalMedical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research HospitalAbstract Cancer stem cells (CSCs) are responsible for colorectal cancer (CRC) chemoresistance, recurrence, and metastasis. Therefore, identifying molecular stemness targets that are involved in tumor growth is crucial for effective treatment. Here, we performed an extensive in vitro and in vivo molecular and functional characterization, revealing the pivotal role of the lysine methyltransferase SET and MYND Domain Containing 3 (SMYD3) in colorectal cancer stem cell (CRC-SC) biology. Specifically, we showed that SMYD3 interacts with and methylates c-MYC at K158 and K163, thereby modulating its transcriptional activity, which is implicated in stemness and colorectal malignancy. Our in vitro data suggest that SMYD3 pharmacological inhibition or its stable genetic ablation affects the clonogenic and self-renewal potential of patient-derived CRC-SCs and organoids by altering their molecular signature. Moreover, we found that SMYD3 stable knock-out or pharmacological inhibition drastically reduces CRC tumorigenicity in vivo and CRC-SC metastatic potential. Overall, our findings identify SMYD3 as a promising therapeutic target acting directly on c-MYC, with potential implications for countering CRC-SC proliferation and metastatic dissemination.https://doi.org/10.1038/s41392-025-02290-z |
| spellingShingle | Martina Lepore Signorile Elisabetta Di Nicola Giovanna Forte Paola Sanese Candida Fasano Vittoria Disciglio Katia De Marco Marialaura Latrofa Loris De Cecco Marica Ficorilli Marta Lucchetta Erica Torchia Chiara Dossena Giusy Bianco Vito Spilotro Claudia Ferroni Nicoletta Labarile Raffaele Armentano Francesco Albano Anna Mestice Gianluigi Gigante Valerio Lantone Giuliano Lantone Leonardo Vincenti Alberto Del Rio Greta Varchi Valentina Grossi Cristiano Simone Tailoring a novel colorectal cancer stem cell-targeted therapy by inhibiting the SMYD3/c-MYC axis Signal Transduction and Targeted Therapy |
| title | Tailoring a novel colorectal cancer stem cell-targeted therapy by inhibiting the SMYD3/c-MYC axis |
| title_full | Tailoring a novel colorectal cancer stem cell-targeted therapy by inhibiting the SMYD3/c-MYC axis |
| title_fullStr | Tailoring a novel colorectal cancer stem cell-targeted therapy by inhibiting the SMYD3/c-MYC axis |
| title_full_unstemmed | Tailoring a novel colorectal cancer stem cell-targeted therapy by inhibiting the SMYD3/c-MYC axis |
| title_short | Tailoring a novel colorectal cancer stem cell-targeted therapy by inhibiting the SMYD3/c-MYC axis |
| title_sort | tailoring a novel colorectal cancer stem cell targeted therapy by inhibiting the smyd3 c myc axis |
| url | https://doi.org/10.1038/s41392-025-02290-z |
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