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SUMO E3 ligase MUL1 inhibits lymph node metastasis of bladder cancer by mediating mitochondrial HSPA9 translocation.
- Source :
-
International journal of biological sciences [Int J Biol Sci] 2024 Jul 15; Vol. 20 (10), pp. 3986-4006. Date of Electronic Publication: 2024 Jul 15 (Print Publication: 2024). - Publication Year :
- 2024
-
Abstract
- Lymph node (LN) metastasis is the dominant cause of death in bladder cancer (BCa) patients, but the underlying mechanism remains largely unknown. In recent years, accumulating studies have confirmed that bidirectional mitochondria-nucleus communication is essential for sustaining multiple function of mitochondria. However, little has been studied regarding whether and how the translocation of mitochondrial proteins is involved in LN metastasis. In this study, we first identified that the SUMO E3 ligase MUL1 was significantly downregulated in LN-metastatic BCa tissues and correlated with a good prognosis. Mechanistically, MUL1 SUMOylated HSPA9 at the K612 residue, leading to HSPA9 export from mitochondria and interaction with SUZ12 and in the nucleus. Consequently, MUL1 induced the ubiquitination-mediated degradation of SUZ12 and EZH2 and induced downstream STAT3 pathway inhibition in a HSPA9-dependent manner. Importantly, mutation of HSPA9 SUMO-conjugation motifs limited the translocation of mitochondrial HSPA9 and blocked the HSPA9-SUZ12 and HSPA9-EZH2 interactions. With mutation of the HSPA9 K612 site, the suppressive role of MUL1 overexpression was lost in BCa cells. Further in vitro and in vivo assays revealed that MUL1 inhibits the metastasis and proliferation of BCa cells. Overall, our study reveals a novel function and molecular mechanism of SUMO E3 ligases in LN metastasis.<br />Competing Interests: Competing Interests: The authors have declared that no competing interest exists.<br /> (© The author(s).)
- Subjects :
- Humans
Cell Line, Tumor
Mitochondria metabolism
Animals
Mice
Mice, Inbred BALB C
Mice, Nude
Male
Sumoylation
Female
Mitochondrial Proteins
Urinary Bladder Neoplasms metabolism
Urinary Bladder Neoplasms pathology
Urinary Bladder Neoplasms genetics
Ubiquitin-Protein Ligases metabolism
Ubiquitin-Protein Ligases genetics
HSP70 Heat-Shock Proteins metabolism
HSP70 Heat-Shock Proteins genetics
Lymphatic Metastasis
Subjects
Details
- Language :
- English
- ISSN :
- 1449-2288
- Volume :
- 20
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- International journal of biological sciences
- Publication Type :
- Academic Journal
- Accession number :
- 39113711
- Full Text :
- https://doi.org/10.7150/ijbs.98772