Glucose-induced STUB1-GOT2 axis promotes aspartate synthesis and mitochondrial dysfunction in bladder cancer
Abstract Aberrant glucose metabolism, a characteristic of malignant tumors, contributes to the development and progression of bladder cancer (BCa). However, the underlying mechanism by which aberrant glucose metabolism promotes BCa progression is still incompletely understood. Here, we demonstrate t...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-07-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07840-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849331635636404224 |
|---|---|
| author | Yunqiang Xiong Qianxi Dong Hongji Hu Zhongqi Li Xiangpeng Zhan Fuchun Zheng Hao Wan Jiahao Liu Shuyu Wu Wang Pan Ruize Yuan Jing Xiong Ju Guo Songhui Xu Bin Fu |
| author_facet | Yunqiang Xiong Qianxi Dong Hongji Hu Zhongqi Li Xiangpeng Zhan Fuchun Zheng Hao Wan Jiahao Liu Shuyu Wu Wang Pan Ruize Yuan Jing Xiong Ju Guo Songhui Xu Bin Fu |
| author_sort | Yunqiang Xiong |
| collection | DOAJ |
| description | Abstract Aberrant glucose metabolism, a characteristic of malignant tumors, contributes to the development and progression of bladder cancer (BCa). However, the underlying mechanism by which aberrant glucose metabolism promotes BCa progression is still incompletely understood. Here, we demonstrate that low levels of STUB1 are associated with worse progression and poor prognosis of BCa patients. STUB1 overexpression attenuates BCa cell proliferation, migration and amino acid metabolism, especial aspartate metabolism. Mechanistically, we identify that STUB1 induces K6- and K48-linked polyubiquitination of GOT2 at K73 lysine residue to decrease its stability, which attenuates mitochondrial aspartate (Asp) synthesis and regulates mitochondrial dysfunction. GOT2 was significantly up-regulated in BCa tissues and negatively associated with STUB1 expression. Furthermore, we reveal that high glucose stress promotes Asp synthesis and tumor growth through STUB1-GOT2 axis. Collectively, our findings identify that STUB1-GOT2 axis is an important regulator for maintaining Asp synthesis and mitochondrial function in BCa cell growth, which highlights that targeting STUB1-GOT2 axis could be a valuable strategy to ameliorate BCa progression by inhibiting amino acid metabolic function. |
| format | Article |
| id | doaj-art-4568f85bb4ee4901a2e397b0c283acec |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-4568f85bb4ee4901a2e397b0c283acec2025-08-20T03:46:28ZengNature Publishing GroupCell Death and Disease2041-48892025-07-0116111310.1038/s41419-025-07840-5Glucose-induced STUB1-GOT2 axis promotes aspartate synthesis and mitochondrial dysfunction in bladder cancerYunqiang Xiong0Qianxi Dong1Hongji Hu2Zhongqi Li3Xiangpeng Zhan4Fuchun Zheng5Hao Wan6Jiahao Liu7Shuyu Wu8Wang Pan9Ruize Yuan10Jing Xiong11Ju Guo12Songhui Xu13Bin Fu14Department of Urology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityDepartment of Urology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityDepartment of Urology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityDepartment of Urology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityDepartment of Urology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityDepartment of Urology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityDepartment of Urology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityDepartment of Urology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityDepartment of Urology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityCollege of Chemical and Environmental Engineering, Shanghai Institute of TechnologyDepartment of Urology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityDepartment of Urology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityDepartment of Urology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityDepartment of Urology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityDepartment of Urology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityAbstract Aberrant glucose metabolism, a characteristic of malignant tumors, contributes to the development and progression of bladder cancer (BCa). However, the underlying mechanism by which aberrant glucose metabolism promotes BCa progression is still incompletely understood. Here, we demonstrate that low levels of STUB1 are associated with worse progression and poor prognosis of BCa patients. STUB1 overexpression attenuates BCa cell proliferation, migration and amino acid metabolism, especial aspartate metabolism. Mechanistically, we identify that STUB1 induces K6- and K48-linked polyubiquitination of GOT2 at K73 lysine residue to decrease its stability, which attenuates mitochondrial aspartate (Asp) synthesis and regulates mitochondrial dysfunction. GOT2 was significantly up-regulated in BCa tissues and negatively associated with STUB1 expression. Furthermore, we reveal that high glucose stress promotes Asp synthesis and tumor growth through STUB1-GOT2 axis. Collectively, our findings identify that STUB1-GOT2 axis is an important regulator for maintaining Asp synthesis and mitochondrial function in BCa cell growth, which highlights that targeting STUB1-GOT2 axis could be a valuable strategy to ameliorate BCa progression by inhibiting amino acid metabolic function.https://doi.org/10.1038/s41419-025-07840-5 |
| spellingShingle | Yunqiang Xiong Qianxi Dong Hongji Hu Zhongqi Li Xiangpeng Zhan Fuchun Zheng Hao Wan Jiahao Liu Shuyu Wu Wang Pan Ruize Yuan Jing Xiong Ju Guo Songhui Xu Bin Fu Glucose-induced STUB1-GOT2 axis promotes aspartate synthesis and mitochondrial dysfunction in bladder cancer Cell Death and Disease |
| title | Glucose-induced STUB1-GOT2 axis promotes aspartate synthesis and mitochondrial dysfunction in bladder cancer |
| title_full | Glucose-induced STUB1-GOT2 axis promotes aspartate synthesis and mitochondrial dysfunction in bladder cancer |
| title_fullStr | Glucose-induced STUB1-GOT2 axis promotes aspartate synthesis and mitochondrial dysfunction in bladder cancer |
| title_full_unstemmed | Glucose-induced STUB1-GOT2 axis promotes aspartate synthesis and mitochondrial dysfunction in bladder cancer |
| title_short | Glucose-induced STUB1-GOT2 axis promotes aspartate synthesis and mitochondrial dysfunction in bladder cancer |
| title_sort | glucose induced stub1 got2 axis promotes aspartate synthesis and mitochondrial dysfunction in bladder cancer |
| url | https://doi.org/10.1038/s41419-025-07840-5 |
| work_keys_str_mv | AT yunqiangxiong glucoseinducedstub1got2axispromotesaspartatesynthesisandmitochondrialdysfunctioninbladdercancer AT qianxidong glucoseinducedstub1got2axispromotesaspartatesynthesisandmitochondrialdysfunctioninbladdercancer AT hongjihu glucoseinducedstub1got2axispromotesaspartatesynthesisandmitochondrialdysfunctioninbladdercancer AT zhongqili glucoseinducedstub1got2axispromotesaspartatesynthesisandmitochondrialdysfunctioninbladdercancer AT xiangpengzhan glucoseinducedstub1got2axispromotesaspartatesynthesisandmitochondrialdysfunctioninbladdercancer AT fuchunzheng glucoseinducedstub1got2axispromotesaspartatesynthesisandmitochondrialdysfunctioninbladdercancer AT haowan glucoseinducedstub1got2axispromotesaspartatesynthesisandmitochondrialdysfunctioninbladdercancer AT jiahaoliu glucoseinducedstub1got2axispromotesaspartatesynthesisandmitochondrialdysfunctioninbladdercancer AT shuyuwu glucoseinducedstub1got2axispromotesaspartatesynthesisandmitochondrialdysfunctioninbladdercancer AT wangpan glucoseinducedstub1got2axispromotesaspartatesynthesisandmitochondrialdysfunctioninbladdercancer AT ruizeyuan glucoseinducedstub1got2axispromotesaspartatesynthesisandmitochondrialdysfunctioninbladdercancer AT jingxiong glucoseinducedstub1got2axispromotesaspartatesynthesisandmitochondrialdysfunctioninbladdercancer AT juguo glucoseinducedstub1got2axispromotesaspartatesynthesisandmitochondrialdysfunctioninbladdercancer AT songhuixu glucoseinducedstub1got2axispromotesaspartatesynthesisandmitochondrialdysfunctioninbladdercancer AT binfu glucoseinducedstub1got2axispromotesaspartatesynthesisandmitochondrialdysfunctioninbladdercancer |