N6-methyladenosine in 28S rRNA promotes oncogenic mRNA translation and tyrosine catabolism
Summary: Aberrant N6-methyladenosine (m6A) modification on mRNA results in dysregulated mRNA translation and cancer progression; however, the role of m6A modification on rRNA remains unclear in cancers. Here, we show that ZCCHC4 and its mediated m6A modification on 28S rRNA are upregulated in variou...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724014906 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846099859211288576 |
|---|---|
| author | Binbin Chen Li Li Ying Huang Jieyi Ma Fei Ji Yilin Chen Lirong Wu Hao Peng |
| author_facet | Binbin Chen Li Li Ying Huang Jieyi Ma Fei Ji Yilin Chen Lirong Wu Hao Peng |
| author_sort | Binbin Chen |
| collection | DOAJ |
| description | Summary: Aberrant N6-methyladenosine (m6A) modification on mRNA results in dysregulated mRNA translation and cancer progression; however, the role of m6A modification on rRNA remains unclear in cancers. Here, we show that ZCCHC4 and its mediated m6A modification on 28S rRNA are upregulated in various cancers and correlated with poor survival. Functionally, ZCCHC4 promotes intrahepatic cholangiocarcinoma (ICC) progression via its catalytic activity. Mechanistically, tether of the N6-adenineMIase domain of ZCCHC4 to the m6A site on 28S rRNA facilitates the binding of the zf-GRF-containing domain to eIF3G in the translation initiation complex and the binding of zf-DHHC-containing domain to the 3′ UTR of mRNA, therefore facilitating mRNA circularization and translation. Further analysis reveals that HPD mediates ZCCHC4’s functions on tyrosine catabolism and ICC progression, and targeting HPD inhibits ICC progression in vivo. Overall, our findings uncover insights underlying mRNA translation control and provide a molecular basis for targeting the ZCCHC4-HPD axis in ICC. |
| format | Article |
| id | doaj-art-e7f7f2cd0a8c4cc2b6c9c404232da5ef |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-e7f7f2cd0a8c4cc2b6c9c404232da5ef2024-12-31T04:13:03ZengElsevierCell Reports2211-12472025-01-01441115139N6-methyladenosine in 28S rRNA promotes oncogenic mRNA translation and tyrosine catabolismBinbin Chen0Li Li1Ying Huang2Jieyi Ma3Fei Ji4Yilin Chen5Lirong Wu6Hao Peng7State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China; Department of Clinical Nutrition, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. ChinaDepartment of Breast Center, Wuzhou Red Cross Hospital, 3-1 Xinxing First Road, Wuzhou 543001, P.R. ChinaState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China; Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. ChinaLaboratory of General Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Breast Cancer, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 106 Zhongshan Er Road, Yuexiu District, Guangzhou 510080, P.R. ChinaDepartment of Breast Cancer, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 106 Zhongshan Er Road, Yuexiu District, Guangzhou 510080, P.R. ChinaDepartment of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China; Corresponding authorDepartment of Breast Cancer, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 106 Zhongshan Er Road, Yuexiu District, Guangzhou 510080, P.R. China; Corresponding authorSummary: Aberrant N6-methyladenosine (m6A) modification on mRNA results in dysregulated mRNA translation and cancer progression; however, the role of m6A modification on rRNA remains unclear in cancers. Here, we show that ZCCHC4 and its mediated m6A modification on 28S rRNA are upregulated in various cancers and correlated with poor survival. Functionally, ZCCHC4 promotes intrahepatic cholangiocarcinoma (ICC) progression via its catalytic activity. Mechanistically, tether of the N6-adenineMIase domain of ZCCHC4 to the m6A site on 28S rRNA facilitates the binding of the zf-GRF-containing domain to eIF3G in the translation initiation complex and the binding of zf-DHHC-containing domain to the 3′ UTR of mRNA, therefore facilitating mRNA circularization and translation. Further analysis reveals that HPD mediates ZCCHC4’s functions on tyrosine catabolism and ICC progression, and targeting HPD inhibits ICC progression in vivo. Overall, our findings uncover insights underlying mRNA translation control and provide a molecular basis for targeting the ZCCHC4-HPD axis in ICC.http://www.sciencedirect.com/science/article/pii/S2211124724014906CP: Molecular biology |
| spellingShingle | Binbin Chen Li Li Ying Huang Jieyi Ma Fei Ji Yilin Chen Lirong Wu Hao Peng N6-methyladenosine in 28S rRNA promotes oncogenic mRNA translation and tyrosine catabolism Cell Reports CP: Molecular biology |
| title | N6-methyladenosine in 28S rRNA promotes oncogenic mRNA translation and tyrosine catabolism |
| title_full | N6-methyladenosine in 28S rRNA promotes oncogenic mRNA translation and tyrosine catabolism |
| title_fullStr | N6-methyladenosine in 28S rRNA promotes oncogenic mRNA translation and tyrosine catabolism |
| title_full_unstemmed | N6-methyladenosine in 28S rRNA promotes oncogenic mRNA translation and tyrosine catabolism |
| title_short | N6-methyladenosine in 28S rRNA promotes oncogenic mRNA translation and tyrosine catabolism |
| title_sort | n6 methyladenosine in 28s rrna promotes oncogenic mrna translation and tyrosine catabolism |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724014906 |
| work_keys_str_mv | AT binbinchen n6methyladenosinein28srrnapromotesoncogenicmrnatranslationandtyrosinecatabolism AT lili n6methyladenosinein28srrnapromotesoncogenicmrnatranslationandtyrosinecatabolism AT yinghuang n6methyladenosinein28srrnapromotesoncogenicmrnatranslationandtyrosinecatabolism AT jieyima n6methyladenosinein28srrnapromotesoncogenicmrnatranslationandtyrosinecatabolism AT feiji n6methyladenosinein28srrnapromotesoncogenicmrnatranslationandtyrosinecatabolism AT yilinchen n6methyladenosinein28srrnapromotesoncogenicmrnatranslationandtyrosinecatabolism AT lirongwu n6methyladenosinein28srrnapromotesoncogenicmrnatranslationandtyrosinecatabolism AT haopeng n6methyladenosinein28srrnapromotesoncogenicmrnatranslationandtyrosinecatabolism |