Both SUMOylation and ubiquitination of TFE3 fusion protein regulated by androgen receptor are the potential target in the therapy of Xp11.2 translocation renal cell carcinoma
ABSTRACT Background The aggressiveness of renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusion (Xp11.2 translocation RCC [Xp11.2 tRCC]) is age‐dependent, which is similar to the overall trend of reproductive endocrine hormones. Therefore, this study focused on the effect...
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Wiley
2022-04-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.797 |
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| author | Ning Liu Yi Chen Lei Yang Qiancheng Shi Yanwen Lu Wenliang Ma Xiaodong Han Hongqian Guo Dongmei Li, Weidong Gan, |
| author_facet | Ning Liu Yi Chen Lei Yang Qiancheng Shi Yanwen Lu Wenliang Ma Xiaodong Han Hongqian Guo Dongmei Li, Weidong Gan, |
| author_sort | Ning Liu |
| collection | DOAJ |
| description | ABSTRACT Background The aggressiveness of renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusion (Xp11.2 translocation RCC [Xp11.2 tRCC]) is age‐dependent, which is similar to the overall trend of reproductive endocrine hormones. Therefore, this study focused on the effect and potential mechanism of androgen and androgen receptor (AR) on the progression of Xp11.2 tRCC. Methods The effects of androgen and AR on the proliferation and migration of Xp11.2 tRCC cells were first evaluated utilising Xp11.2 tRCC cell lines and tissues. Because Transcription factor enhancer 3 (TFE3) fusion proteins play a key role in Xp11.2 tRCC, we focused on the regulatory role of AR and TFE3 expression and transcriptional activity. Results When Xp11.2 tRCC cells were treated with dihydrotestosterone, increased cell proliferation, invasion and migration were observed. Compared with clear cell RCC, the positive rate of AR in Xp11.2 tRCC tissues was higher, and its expression was negatively associated with the progression‐free survival of Xp11.2 tRCC. Further studies revealed that AR could positively regulate the transcriptional activity of TFE3 fusion proteins by small ubiquitin‐related modifier (SUMO)‐specific protease 1, inducing the deSUMOylation of TFE3 fusion. On the other hand, UCHL1 negatively regulated by AR plays a role in the deubiquitination degradation of the PRCC‐TFE3 fusion protein. Therefore, the combination of the AR inhibitor MDV3100 and the UCHL1 inhibitor 6RK73 was effective in delaying the progression of Xp11.2 tRCC, especially PRCC‐TFE3 tRCC. Conclusions Androgen and AR function as facilitators in Xp11.2 tRCC progression and may be a novel therapeutic target for Xp11.2 tRCC. The combined use of AR antagonist MDV3100 and UCHL1 inhibitor 6RK73 increased both the SUMOylation and ubiquitination of the PRCC‐TFE3 fusion protein |
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| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-12-10T09:59:57Z |
| publishDate | 2022-04-01 |
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| series | Clinical and Translational Medicine |
| spelling | doaj.art-6bf2b6d0f1fe461db7ada839f1f1f2782022-12-22T01:53:23ZengWileyClinical and Translational Medicine2001-13262022-04-01124n/an/a10.1002/ctm2.797Both SUMOylation and ubiquitination of TFE3 fusion protein regulated by androgen receptor are the potential target in the therapy of Xp11.2 translocation renal cell carcinomaNing Liu0Yi Chen1Lei Yang2Qiancheng Shi3Yanwen Lu4Wenliang Ma5Xiaodong Han6Hongqian Guo7Dongmei Li,8Weidong Gan,9Department of Urology Affiliated Drum Tower Hospital of Medical School of Nanjing University Nanjing Jiangsu ChinaImmunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science Medical School Nanjing University Nanjing Jiangsu ChinaImmunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science Medical School Nanjing University Nanjing Jiangsu ChinaDepartment of Urology Affiliated Sir Run Run Hospital Nanjing Medical University Nanjing Jiangsu ChinaDepartment of Urology Affiliated Drum Tower Hospital of Medical School of Nanjing University Nanjing Jiangsu ChinaDepartment of Urology Affiliated Drum Tower Hospital of Medical School of Nanjing University Nanjing Jiangsu ChinaImmunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science Medical School Nanjing University Nanjing Jiangsu ChinaDepartment of Urology Affiliated Drum Tower Hospital of Medical School of Nanjing University Nanjing Jiangsu ChinaImmunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science Medical School Nanjing University Nanjing Jiangsu ChinaDepartment of Urology Affiliated Drum Tower Hospital of Medical School of Nanjing University Nanjing Jiangsu ChinaABSTRACT Background The aggressiveness of renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusion (Xp11.2 translocation RCC [Xp11.2 tRCC]) is age‐dependent, which is similar to the overall trend of reproductive endocrine hormones. Therefore, this study focused on the effect and potential mechanism of androgen and androgen receptor (AR) on the progression of Xp11.2 tRCC. Methods The effects of androgen and AR on the proliferation and migration of Xp11.2 tRCC cells were first evaluated utilising Xp11.2 tRCC cell lines and tissues. Because Transcription factor enhancer 3 (TFE3) fusion proteins play a key role in Xp11.2 tRCC, we focused on the regulatory role of AR and TFE3 expression and transcriptional activity. Results When Xp11.2 tRCC cells were treated with dihydrotestosterone, increased cell proliferation, invasion and migration were observed. Compared with clear cell RCC, the positive rate of AR in Xp11.2 tRCC tissues was higher, and its expression was negatively associated with the progression‐free survival of Xp11.2 tRCC. Further studies revealed that AR could positively regulate the transcriptional activity of TFE3 fusion proteins by small ubiquitin‐related modifier (SUMO)‐specific protease 1, inducing the deSUMOylation of TFE3 fusion. On the other hand, UCHL1 negatively regulated by AR plays a role in the deubiquitination degradation of the PRCC‐TFE3 fusion protein. Therefore, the combination of the AR inhibitor MDV3100 and the UCHL1 inhibitor 6RK73 was effective in delaying the progression of Xp11.2 tRCC, especially PRCC‐TFE3 tRCC. Conclusions Androgen and AR function as facilitators in Xp11.2 tRCC progression and may be a novel therapeutic target for Xp11.2 tRCC. The combined use of AR antagonist MDV3100 and UCHL1 inhibitor 6RK73 increased both the SUMOylation and ubiquitination of the PRCC‐TFE3 fusion proteinhttps://doi.org/10.1002/ctm2.797progressionSUMOylationTFE3translocation RCCubiquitination |
| spellingShingle | Ning Liu Yi Chen Lei Yang Qiancheng Shi Yanwen Lu Wenliang Ma Xiaodong Han Hongqian Guo Dongmei Li, Weidong Gan, Both SUMOylation and ubiquitination of TFE3 fusion protein regulated by androgen receptor are the potential target in the therapy of Xp11.2 translocation renal cell carcinoma Clinical and Translational Medicine progression SUMOylation TFE3 translocation RCC ubiquitination |
| title | Both SUMOylation and ubiquitination of TFE3 fusion protein regulated by androgen receptor are the potential target in the therapy of Xp11.2 translocation renal cell carcinoma |
| title_full | Both SUMOylation and ubiquitination of TFE3 fusion protein regulated by androgen receptor are the potential target in the therapy of Xp11.2 translocation renal cell carcinoma |
| title_fullStr | Both SUMOylation and ubiquitination of TFE3 fusion protein regulated by androgen receptor are the potential target in the therapy of Xp11.2 translocation renal cell carcinoma |
| title_full_unstemmed | Both SUMOylation and ubiquitination of TFE3 fusion protein regulated by androgen receptor are the potential target in the therapy of Xp11.2 translocation renal cell carcinoma |
| title_short | Both SUMOylation and ubiquitination of TFE3 fusion protein regulated by androgen receptor are the potential target in the therapy of Xp11.2 translocation renal cell carcinoma |
| title_sort | both sumoylation and ubiquitination of tfe3 fusion protein regulated by androgen receptor are the potential target in the therapy of xp11 2 translocation renal cell carcinoma |
| topic | progression SUMOylation TFE3 translocation RCC ubiquitination |
| url | https://doi.org/10.1002/ctm2.797 |
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