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| Status |
Public on Mar 19, 2024 |
| Title |
Von Hippel Lindau tumor suppressor controls m6A-dependent gene expression in renal tumorigenesis |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Other
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| Summary |
N6âMethyladenosine (m6A) is the most abundant internal postâtranslational modification, and its contribution to cancer evolution has recently been appreciated. Renal cancer is the most common adult genitourinary cancer, of which ~85% is accounted for by the clear cell subtype (ccRCC) characterized by VHL loss. In this study, we demonstrate for the first time that VHL binds with m6A enzymatic complex proteins and promotes METTL3-METTL14 complex formation, and VHL depletion suppresses mRNA m6A modification. m6A RIP-seq coupled with RNA-seq in renal cells with or without VHL allowed us to identify a selection of genes whose expression may be regulated by m6A. Specifically, PIK3R3 is identified to be one critical gene whose mRNA stability is regulated by VHL in a m6A-dependent but HIF-independent manner. Functionally, PIK3R3 depletion promotes renal cancer cell growth and orthotopic tumor growth while vice versa. Mechanistically, PIK3R3 suppresses tumor growth by restraining PI3K/AKT activity. Taken together, we propose a new mechanism by which VHL regulates m6A through modulation of METTL3-METTL14 protein complex formation, thereby promoting PIK3R3 mRNA stability and protein level that is critical for regulating ccRCC tumorigenesis.
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| Overall design |
m6A RIP-seq and RNA-seq between normal (sgCtrl) and VHL KO (sgVHL_sg1 or sgVHL_sg2) HKC cells.
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| Web link |
https://doi.org/10.1172/jci175703
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| Contributor(s) |
Zhang C, Yu M, Hepperla AJ, Zhang Z, Raj R, Zhong H, Zhou J, Hu L, Fang J, Liu H, Liang Q, Jia L, Liao C, Xi S, Simon JM, Xu K, Liu Z, Nam Y, Kapur P, Zhang Q |
| Citation(s) |
38618952 |
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| Submission date |
Aug 02, 2023 |
| Last update date |
Jun 24, 2024 |
| Contact name |
Austin J Hepperla |
| E-mail(s) |
hepperla@unc.edu
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| Organization name |
University of North Carolina at Chapel Hill
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| Department |
Genetics
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| Street address |
7018B Mary Ellen Jones Building
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| City |
Chapel Hill |
| State/province |
NC |
| ZIP/Postal code |
27599 |
| Country |
USA |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (21)
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| Relations |
| BioProject |
PRJNA1001349 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE239892_HKC_sgCtrl_MeRIP_Rep1.bw |
223.2 Mb |
(ftp)(http) |
BW |
| GSE239892_HKC_sgCtrl_MeRIP_Rep2.bw |
232.3 Mb |
(ftp)(http) |
BW |
| GSE239892_HKC_sgCtrl_MeRIP_Rep3.bw |
166.2 Mb |
(ftp)(http) |
BW |
| GSE239892_HKC_sgCtrl_MeRIP_input.bw |
216.1 Mb |
(ftp)(http) |
BW |
| GSE239892_HKC_sgCtrl_m6A_peaks_MeTDiff.xlsx |
2.1 Mb |
(ftp)(http) |
XLSX |
| GSE239892_HKC_sgCtrl_sgVHL_DESeq2_feature_counts.xlsx |
5.2 Mb |
(ftp)(http) |
XLSX |
| GSE239892_HKC_sgCtrl_sgVHL_m6A_sites_MATK.xlsx |
7.4 Mb |
(ftp)(http) |
XLSX |
| GSE239892_HKC_sgVHL_sg1_MeRIP_Rep1.bw |
203.6 Mb |
(ftp)(http) |
BW |
| GSE239892_HKC_sgVHL_sg1_MeRIP_Rep2.bw |
161.3 Mb |
(ftp)(http) |
BW |
| GSE239892_HKC_sgVHL_sg1_MeRIP_Rep3.bw |
179.9 Mb |
(ftp)(http) |
BW |
| GSE239892_HKC_sgVHL_sg1_MeRIP_input.bw |
188.7 Mb |
(ftp)(http) |
BW |
| GSE239892_HKC_sgVHL_sg1_m6A_peaks_MeTDiff.xlsx |
2.2 Mb |
(ftp)(http) |
XLSX |
| GSE239892_HKC_sgVHL_sg1_vs_sgCtrl_diff_peaks_MeTDiff.xlsx |
507.3 Kb |
(ftp)(http) |
XLSX |
| GSE239892_HKC_sgVHL_sg2_MeRIP_Rep1.bw |
215.7 Mb |
(ftp)(http) |
BW |
| GSE239892_HKC_sgVHL_sg2_MeRIP_Rep2.bw |
212.9 Mb |
(ftp)(http) |
BW |
| GSE239892_HKC_sgVHL_sg2_MeRIP_Rep3.bw |
190.5 Mb |
(ftp)(http) |
BW |
| GSE239892_HKC_sgVHL_sg2_MeRIP_input.bw |
238.7 Mb |
(ftp)(http) |
BW |
| GSE239892_HKC_sgVHL_sg2_m6A_peaks_MeTDiff.xlsx |
2.0 Mb |
(ftp)(http) |
XLSX |
| GSE239892_HKC_sgVHL_sg2_vs_sgCtrl_diff_peaks_MeTDiff.xlsx |
579.8 Kb |
(ftp)(http) |
XLSX |
| GSE239892_HKC_sgVHL_vs_sgCtrl_DESeq2_diff_genes.xlsx |
1.5 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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