The RNA-binding protein KSRP aggravates malignant progression of clear cell renal cell carcinoma through transcriptional inhibition and post-transcriptional destabilization of the NEDD4L ubiquitin ligase
Abstract Background KH-type splicing regulatory protein (KHSRP, also called KSRP), a versatile RNA-binding protein, plays a critical role in various physiological and pathological conditions through modulating gene expressions at multiple levels. However, the role of KSRP in clear cell renal cell ca...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-08-01
|
| Series: | Journal of Biomedical Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12929-023-00949-9 |
| _version_ | 1797557469377986560 |
|---|---|
| author | Yi-Chieh Yang Yung-Wei Lin Wei-Jiunn Lee Feng-Ru Lai Kuo-Hao Ho Chih-Ying Chu Kuo-Tai Hua Ji-Qing Chen Min-Che Tung Michael Hsiao Yu-Ching Wen Ming-Hsien Chien |
| author_facet | Yi-Chieh Yang Yung-Wei Lin Wei-Jiunn Lee Feng-Ru Lai Kuo-Hao Ho Chih-Ying Chu Kuo-Tai Hua Ji-Qing Chen Min-Che Tung Michael Hsiao Yu-Ching Wen Ming-Hsien Chien |
| author_sort | Yi-Chieh Yang |
| collection | DOAJ |
| description | Abstract Background KH-type splicing regulatory protein (KHSRP, also called KSRP), a versatile RNA-binding protein, plays a critical role in various physiological and pathological conditions through modulating gene expressions at multiple levels. However, the role of KSRP in clear cell renal cell carcinoma (ccRCC) remains poorly understood. Methods KSRP expression was detected by a ccRCC tissue microarray and evaluated by an in silico analysis. Cell loss-of-function and gain-of-function, colony-formation, anoikis, and transwell assays, and an orthotopic bioluminescent xenograft model were conducted to determine the functional role of KRSP in ccRCC progression. Micro (mi)RNA and complementary (c)DNA microarrays were used to identify downstream targets of KSRP. Western blotting, quantitative real-time polymerase chain reaction, and promoter- and 3-untranslated region (3'UTR)-luciferase reporter assays were employed to validate the underlying mechanisms of KSRP which aggravate progression of ccRCC. Results Our results showed that dysregulated high levels of KSRP were correlated with advanced clinical stages, larger tumor sizes, recurrence, and poor prognoses of ccRCC. Neural precursor cell-expressed developmentally downregulated 4 like (NEDD4L) was identified as a novel target of KSRP, which can reverse the protumorigenic and prometastatic characteristics as well as epithelial-mesenchymal transition (EMT) promotion by KSRP in vitro and in vivo. Molecular studies revealed that KSRP can decrease NEDD4L messenger (m)RNA stability via inducing mir-629-5p upregulation and directly targeting the AU-rich elements (AREs) of the 3’UTR. Moreover, KSRP was shown to transcriptionally suppress NEDD4L via inducing the transcriptional repressor, Wilm's tumor 1 (WT1). In the clinic, ccRCC samples revealed a positive correlation between KSRP and mesenchymal-related genes, and patients expressing high KSRP and low NEDD4L had the worst prognoses. Conclusion The current findings unveil novel mechanisms of KSRP which promote malignant progression of ccRCC through transcriptional inhibition and post-transcriptional destabilization of NEDD4L transcripts. Targeting KSRP and its pathways may be a novel pharmaceutical intervention for ccRCC. |
| first_indexed | 2024-03-10T17:17:29Z |
| format | Article |
| id | doaj.art-bd335b0ec28f410dae03d020ff3c22fd |
| institution | Directory Open Access Journal |
| issn | 1423-0127 |
| language | English |
| last_indexed | 2024-03-10T17:17:29Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Biomedical Science |
| spelling | doaj.art-bd335b0ec28f410dae03d020ff3c22fd2023-11-20T10:28:02ZengBMCJournal of Biomedical Science1423-01272023-08-0130112310.1186/s12929-023-00949-9The RNA-binding protein KSRP aggravates malignant progression of clear cell renal cell carcinoma through transcriptional inhibition and post-transcriptional destabilization of the NEDD4L ubiquitin ligaseYi-Chieh Yang0Yung-Wei Lin1Wei-Jiunn Lee2Feng-Ru Lai3Kuo-Hao Ho4Chih-Ying Chu5Kuo-Tai Hua6Ji-Qing Chen7Min-Che Tung8Michael Hsiao9Yu-Ching Wen10Ming-Hsien Chien11Department of Medical Research, Tungs’ Taichung MetroHarbor HospitalInternational Master/PhD Program in Medicine, College of Medicine, Taipei Medical UniversityGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical UniversityGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical UniversityGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical UniversityGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical UniversityGraduate Institute of Toxicology, College of Medicine, National Taiwan UniversityGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical UniversityDepartment of Surgery, Tungs’ Taichung Metro Harbor HospitalGenomics Research Center, Academia SinicaDepartment of Urology, Wan Fang Hospital, Taipei Medical UniversityGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical UniversityAbstract Background KH-type splicing regulatory protein (KHSRP, also called KSRP), a versatile RNA-binding protein, plays a critical role in various physiological and pathological conditions through modulating gene expressions at multiple levels. However, the role of KSRP in clear cell renal cell carcinoma (ccRCC) remains poorly understood. Methods KSRP expression was detected by a ccRCC tissue microarray and evaluated by an in silico analysis. Cell loss-of-function and gain-of-function, colony-formation, anoikis, and transwell assays, and an orthotopic bioluminescent xenograft model were conducted to determine the functional role of KRSP in ccRCC progression. Micro (mi)RNA and complementary (c)DNA microarrays were used to identify downstream targets of KSRP. Western blotting, quantitative real-time polymerase chain reaction, and promoter- and 3-untranslated region (3'UTR)-luciferase reporter assays were employed to validate the underlying mechanisms of KSRP which aggravate progression of ccRCC. Results Our results showed that dysregulated high levels of KSRP were correlated with advanced clinical stages, larger tumor sizes, recurrence, and poor prognoses of ccRCC. Neural precursor cell-expressed developmentally downregulated 4 like (NEDD4L) was identified as a novel target of KSRP, which can reverse the protumorigenic and prometastatic characteristics as well as epithelial-mesenchymal transition (EMT) promotion by KSRP in vitro and in vivo. Molecular studies revealed that KSRP can decrease NEDD4L messenger (m)RNA stability via inducing mir-629-5p upregulation and directly targeting the AU-rich elements (AREs) of the 3’UTR. Moreover, KSRP was shown to transcriptionally suppress NEDD4L via inducing the transcriptional repressor, Wilm's tumor 1 (WT1). In the clinic, ccRCC samples revealed a positive correlation between KSRP and mesenchymal-related genes, and patients expressing high KSRP and low NEDD4L had the worst prognoses. Conclusion The current findings unveil novel mechanisms of KSRP which promote malignant progression of ccRCC through transcriptional inhibition and post-transcriptional destabilization of NEDD4L transcripts. Targeting KSRP and its pathways may be a novel pharmaceutical intervention for ccRCC.https://doi.org/10.1186/s12929-023-00949-9ccRCCProgressionKSRPNEDD4LEMT |
| spellingShingle | Yi-Chieh Yang Yung-Wei Lin Wei-Jiunn Lee Feng-Ru Lai Kuo-Hao Ho Chih-Ying Chu Kuo-Tai Hua Ji-Qing Chen Min-Che Tung Michael Hsiao Yu-Ching Wen Ming-Hsien Chien The RNA-binding protein KSRP aggravates malignant progression of clear cell renal cell carcinoma through transcriptional inhibition and post-transcriptional destabilization of the NEDD4L ubiquitin ligase Journal of Biomedical Science ccRCC Progression KSRP NEDD4L EMT |
| title | The RNA-binding protein KSRP aggravates malignant progression of clear cell renal cell carcinoma through transcriptional inhibition and post-transcriptional destabilization of the NEDD4L ubiquitin ligase |
| title_full | The RNA-binding protein KSRP aggravates malignant progression of clear cell renal cell carcinoma through transcriptional inhibition and post-transcriptional destabilization of the NEDD4L ubiquitin ligase |
| title_fullStr | The RNA-binding protein KSRP aggravates malignant progression of clear cell renal cell carcinoma through transcriptional inhibition and post-transcriptional destabilization of the NEDD4L ubiquitin ligase |
| title_full_unstemmed | The RNA-binding protein KSRP aggravates malignant progression of clear cell renal cell carcinoma through transcriptional inhibition and post-transcriptional destabilization of the NEDD4L ubiquitin ligase |
| title_short | The RNA-binding protein KSRP aggravates malignant progression of clear cell renal cell carcinoma through transcriptional inhibition and post-transcriptional destabilization of the NEDD4L ubiquitin ligase |
| title_sort | rna binding protein ksrp aggravates malignant progression of clear cell renal cell carcinoma through transcriptional inhibition and post transcriptional destabilization of the nedd4l ubiquitin ligase |
| topic | ccRCC Progression KSRP NEDD4L EMT |
| url | https://doi.org/10.1186/s12929-023-00949-9 |
| work_keys_str_mv | AT yichiehyang thernabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT yungweilin thernabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT weijiunnlee thernabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT fengrulai thernabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT kuohaoho thernabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT chihyingchu thernabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT kuotaihua thernabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT jiqingchen thernabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT minchetung thernabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT michaelhsiao thernabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT yuchingwen thernabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT minghsienchien thernabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT yichiehyang rnabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT yungweilin rnabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT weijiunnlee rnabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT fengrulai rnabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT kuohaoho rnabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT chihyingchu rnabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT kuotaihua rnabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT jiqingchen rnabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT minchetung rnabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT michaelhsiao rnabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT yuchingwen rnabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase AT minghsienchien rnabindingproteinksrpaggravatesmalignantprogressionofclearcellrenalcellcarcinomathroughtranscriptionalinhibitionandposttranscriptionaldestabilizationofthenedd4lubiquitinligase |