METTL3-Modulated <i>circUHRF2</i> Promotes Colorectal Cancer Stemness and Metastasis through Increasing <i>DDX27</i> mRNA Stability by Recruiting IGF2BP1
Increasing evidence has implicated that circular RNAs (circRNAs) exert important roles in colorectal cancer (CRC) occurrence and progression. However, the role of a novel circRNA, <i>circUHRF2</i>, remains unknown in CRC. Our work aimed at identifying the functional roles of <i>cir...
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| Format: | Article |
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MDPI AG
2023-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/12/3148 |
| _version_ | 1797436170900078592 |
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| author | Miao Chen Buning Tian Gui Hu Yihang Guo |
| author_facet | Miao Chen Buning Tian Gui Hu Yihang Guo |
| author_sort | Miao Chen |
| collection | DOAJ |
| description | Increasing evidence has implicated that circular RNAs (circRNAs) exert important roles in colorectal cancer (CRC) occurrence and progression. However, the role of a novel circRNA, <i>circUHRF2</i>, remains unknown in CRC. Our work aimed at identifying the functional roles of <i>circUHRF2</i> in CRC and illustrating the potential mechanisms. As assessed by quantitative real-time PCR (qRT-PCR), <i>circUHRF2</i> and methyltransferase-like 3 (METTL3) were highly expressed in CRC specimens and cells. Sanger sequencing and RNase R assays were performed to verify the ring structure of <i>circUHRF2</i>. Notably, aberrantly increased expression of <i>circUHRF2</i> was positively correlated with poor prognosis of CRC patients. Functional experiments indicated that CRC stemness, migration, and epithelial-mesenchymal transition (EMT) were suppressed by the knockdown of <i>circUHRF2</i> or METTL3. Mechanistically, METTL3 enhanced <i>circUHRF2</i> expression through N6-methyladenine (m<sup>6</sup>A) modification. Rescue experiments showed that overexpression of <i>circUHRF2</i> reversed the repressive effect of METTL3 silencing on CRC progression. Moreover, <i>circUHRF2</i> inhibited the loss of DEAD-box helicase 27 (DDX27) protein via promoting the interaction between insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and <i>DDX27</i> mRNA. DDX27 knockdown repressed CRC malignant properties, which was counteracted by <i>circUHRF2</i> overexpression. The in vivo assays in nude mice demonstrated that <i>circUHRF2</i> or METTL3 silencing exerted a suppressive effect on CRC growth and liver metastasis via repressing DDX27 protein expression. Taken together, METTL3-mediated m<sup>6</sup>A modification upregulated <i>circUHRF2</i> and subsequently inhibited loss of DDX27 protein via recruitment of IGF2BP1, which conferred CRC stemness and metastasis. These findings shed light on CRC pathogenesis and suggest <i>circUHRF2</i> as a novel target for CRC treatment. |
| first_indexed | 2024-03-09T10:57:45Z |
| format | Article |
| id | doaj.art-efa95d4700954cefaf44bc2621312ec8 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T10:57:45Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-efa95d4700954cefaf44bc2621312ec82023-12-01T01:31:02ZengMDPI AGCancers2072-66942023-06-011512314810.3390/cancers15123148METTL3-Modulated <i>circUHRF2</i> Promotes Colorectal Cancer Stemness and Metastasis through Increasing <i>DDX27</i> mRNA Stability by Recruiting IGF2BP1Miao Chen0Buning Tian1Gui Hu2Yihang Guo3Department of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha 410013, ChinaDepartment of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha 410013, ChinaDepartment of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha 410013, ChinaDepartment of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha 410013, ChinaIncreasing evidence has implicated that circular RNAs (circRNAs) exert important roles in colorectal cancer (CRC) occurrence and progression. However, the role of a novel circRNA, <i>circUHRF2</i>, remains unknown in CRC. Our work aimed at identifying the functional roles of <i>circUHRF2</i> in CRC and illustrating the potential mechanisms. As assessed by quantitative real-time PCR (qRT-PCR), <i>circUHRF2</i> and methyltransferase-like 3 (METTL3) were highly expressed in CRC specimens and cells. Sanger sequencing and RNase R assays were performed to verify the ring structure of <i>circUHRF2</i>. Notably, aberrantly increased expression of <i>circUHRF2</i> was positively correlated with poor prognosis of CRC patients. Functional experiments indicated that CRC stemness, migration, and epithelial-mesenchymal transition (EMT) were suppressed by the knockdown of <i>circUHRF2</i> or METTL3. Mechanistically, METTL3 enhanced <i>circUHRF2</i> expression through N6-methyladenine (m<sup>6</sup>A) modification. Rescue experiments showed that overexpression of <i>circUHRF2</i> reversed the repressive effect of METTL3 silencing on CRC progression. Moreover, <i>circUHRF2</i> inhibited the loss of DEAD-box helicase 27 (DDX27) protein via promoting the interaction between insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and <i>DDX27</i> mRNA. DDX27 knockdown repressed CRC malignant properties, which was counteracted by <i>circUHRF2</i> overexpression. The in vivo assays in nude mice demonstrated that <i>circUHRF2</i> or METTL3 silencing exerted a suppressive effect on CRC growth and liver metastasis via repressing DDX27 protein expression. Taken together, METTL3-mediated m<sup>6</sup>A modification upregulated <i>circUHRF2</i> and subsequently inhibited loss of DDX27 protein via recruitment of IGF2BP1, which conferred CRC stemness and metastasis. These findings shed light on CRC pathogenesis and suggest <i>circUHRF2</i> as a novel target for CRC treatment.https://www.mdpi.com/2072-6694/15/12/3148colorectal cancerstemnesstumor metastasis<i>circUHRF2</i>DDX27 signalingN6-methyladenine (m<sup>6</sup>A) modification |
| spellingShingle | Miao Chen Buning Tian Gui Hu Yihang Guo METTL3-Modulated <i>circUHRF2</i> Promotes Colorectal Cancer Stemness and Metastasis through Increasing <i>DDX27</i> mRNA Stability by Recruiting IGF2BP1 Cancers colorectal cancer stemness tumor metastasis <i>circUHRF2</i> DDX27 signaling N6-methyladenine (m<sup>6</sup>A) modification |
| title | METTL3-Modulated <i>circUHRF2</i> Promotes Colorectal Cancer Stemness and Metastasis through Increasing <i>DDX27</i> mRNA Stability by Recruiting IGF2BP1 |
| title_full | METTL3-Modulated <i>circUHRF2</i> Promotes Colorectal Cancer Stemness and Metastasis through Increasing <i>DDX27</i> mRNA Stability by Recruiting IGF2BP1 |
| title_fullStr | METTL3-Modulated <i>circUHRF2</i> Promotes Colorectal Cancer Stemness and Metastasis through Increasing <i>DDX27</i> mRNA Stability by Recruiting IGF2BP1 |
| title_full_unstemmed | METTL3-Modulated <i>circUHRF2</i> Promotes Colorectal Cancer Stemness and Metastasis through Increasing <i>DDX27</i> mRNA Stability by Recruiting IGF2BP1 |
| title_short | METTL3-Modulated <i>circUHRF2</i> Promotes Colorectal Cancer Stemness and Metastasis through Increasing <i>DDX27</i> mRNA Stability by Recruiting IGF2BP1 |
| title_sort | mettl3 modulated i circuhrf2 i promotes colorectal cancer stemness and metastasis through increasing i ddx27 i mrna stability by recruiting igf2bp1 |
| topic | colorectal cancer stemness tumor metastasis <i>circUHRF2</i> DDX27 signaling N6-methyladenine (m<sup>6</sup>A) modification |
| url | https://www.mdpi.com/2072-6694/15/12/3148 |
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