MYCN mRNA degradation and cancer suppression by a selective small-molecule inhibitor in MYCN-amplified neuroblastoma
Amplification of the MYCN gene leads to its overexpression at both the mRNA and protein levels. Overexpression of MYCN mRNA may also have an important role in promoting neuroblastoma (NB) beyond the translation of MYCN protein. In the present study, we report a small molecule compound (MX25-1) that...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.1058726/full |
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| author | Tao Liu Lubing Gu Zhongzhi Wu Najah Albadari Wei Li Muxiang Zhou |
| author_facet | Tao Liu Lubing Gu Zhongzhi Wu Najah Albadari Wei Li Muxiang Zhou |
| author_sort | Tao Liu |
| collection | DOAJ |
| description | Amplification of the MYCN gene leads to its overexpression at both the mRNA and protein levels. Overexpression of MYCN mRNA may also have an important role in promoting neuroblastoma (NB) beyond the translation of MYCN protein. In the present study, we report a small molecule compound (MX25-1) that was able to bind to the 3’UTR of MYCN mRNA and induce MYCN mRNA degradation; this resulted in potent cell-growth inhibition and cell death specifically in MYCN-amplified or MYCN 3’UTR overexpressing NB cells. To evaluate the role of MYCN 3’UTR-mediated signals in contributing to the anticancer activity of MX25-1, we examined the status and activation of the tumor suppressor microRNA (miRNA) let-7, which is a target of MYCN 3’UTR in MYCN-amplified NB. We first observed that overexpression of MYCN mRNA was associated with high-level expression of the let-7 oncogenic targets DICER1, ARID3B and HMGA2. Following MYCN mRNA degradation, the expression of DICER1, ARID3B and HMGA2 was downregulated in MX25-1-treated cells. Inhibition of let-7 reversed the downregulation of these oncogenic mRNAs and significantly increased resistance of NB cells to MX25-1. Our results from this study supported the notion that overexpression of MYCN mRNA due to gene amplification has an independent function in NB cell growth and disease progression and suggest that targeting MYCN mRNA may represent an attractive strategy for therapy of MYCN amplified NB, both by inhibiting MYCN’s cell-survival effects and activating the tumor-suppressor effect of let-7. |
| first_indexed | 2024-04-12T06:51:38Z |
| format | Article |
| id | doaj.art-937dacf25a24413bba8b9ec93921e6f2 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T06:51:38Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-937dacf25a24413bba8b9ec93921e6f22022-12-22T03:43:19ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-11-011210.3389/fonc.2022.10587261058726MYCN mRNA degradation and cancer suppression by a selective small-molecule inhibitor in MYCN-amplified neuroblastomaTao Liu0Lubing Gu1Zhongzhi Wu2Najah Albadari3Wei Li4Muxiang Zhou5Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, United StatesDepartment of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, United StatesDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, United StatesDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, United StatesDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, United StatesDepartment of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, United StatesAmplification of the MYCN gene leads to its overexpression at both the mRNA and protein levels. Overexpression of MYCN mRNA may also have an important role in promoting neuroblastoma (NB) beyond the translation of MYCN protein. In the present study, we report a small molecule compound (MX25-1) that was able to bind to the 3’UTR of MYCN mRNA and induce MYCN mRNA degradation; this resulted in potent cell-growth inhibition and cell death specifically in MYCN-amplified or MYCN 3’UTR overexpressing NB cells. To evaluate the role of MYCN 3’UTR-mediated signals in contributing to the anticancer activity of MX25-1, we examined the status and activation of the tumor suppressor microRNA (miRNA) let-7, which is a target of MYCN 3’UTR in MYCN-amplified NB. We first observed that overexpression of MYCN mRNA was associated with high-level expression of the let-7 oncogenic targets DICER1, ARID3B and HMGA2. Following MYCN mRNA degradation, the expression of DICER1, ARID3B and HMGA2 was downregulated in MX25-1-treated cells. Inhibition of let-7 reversed the downregulation of these oncogenic mRNAs and significantly increased resistance of NB cells to MX25-1. Our results from this study supported the notion that overexpression of MYCN mRNA due to gene amplification has an independent function in NB cell growth and disease progression and suggest that targeting MYCN mRNA may represent an attractive strategy for therapy of MYCN amplified NB, both by inhibiting MYCN’s cell-survival effects and activating the tumor-suppressor effect of let-7.https://www.frontiersin.org/articles/10.3389/fonc.2022.1058726/fullMYCNMDM2small-molecule inhibitorneuroblastomacancer |
| spellingShingle | Tao Liu Lubing Gu Zhongzhi Wu Najah Albadari Wei Li Muxiang Zhou MYCN mRNA degradation and cancer suppression by a selective small-molecule inhibitor in MYCN-amplified neuroblastoma Frontiers in Oncology MYCN MDM2 small-molecule inhibitor neuroblastoma cancer |
| title | MYCN mRNA degradation and cancer suppression by a selective small-molecule inhibitor in MYCN-amplified neuroblastoma |
| title_full | MYCN mRNA degradation and cancer suppression by a selective small-molecule inhibitor in MYCN-amplified neuroblastoma |
| title_fullStr | MYCN mRNA degradation and cancer suppression by a selective small-molecule inhibitor in MYCN-amplified neuroblastoma |
| title_full_unstemmed | MYCN mRNA degradation and cancer suppression by a selective small-molecule inhibitor in MYCN-amplified neuroblastoma |
| title_short | MYCN mRNA degradation and cancer suppression by a selective small-molecule inhibitor in MYCN-amplified neuroblastoma |
| title_sort | mycn mrna degradation and cancer suppression by a selective small molecule inhibitor in mycn amplified neuroblastoma |
| topic | MYCN MDM2 small-molecule inhibitor neuroblastoma cancer |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.1058726/full |
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