Augmenting L3MBTL2-induced condensates suppresses tumor growth in osteosarcoma
Li Zhong1,2, Jingxuan Wang1, Wanqi Chen2
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
Abstract:
Osteosarcoma is a highly aggressive cancer and lacks effective therapeutic targets. We found that L3MBTL2 acts as a tumor suppressor by transcriptionally repressing IFIT2 in osteosarcoma. L3MBTL2 recruits the components of Polycomb repressive complex 1.6 to form condensates via both Pho-binding pockets and polybasic regions within carboxyl-terminal intrinsically disordered regions; the L3MBTL2-induced condensates are required for its tumor suppression. Multi-monoubiquitination of L3MBTL2 by UBE2O results in its proteasomal degradation, and the UBE2O/L3MBTL2 axis was crucial for osteosarcoma growth. There is a reverse correlation between L3MBTL2 and UBE2O in osteosarcoma tissues, and higher UBE2O and lower L3MBTL2 are associated with poorer prognosis in osteosarcoma. Pharmacological blockage of UBE2O by arsenic trioxide can enhance L3MBTL2-induced condensates and consequently suppress osteosarcoma growth. Our findings unveil a crucial biological function of L3MBTL2-induced condensates in mediating tumor suppression, proposing the UBE2O-L3MBTL2 axis as a potential cancer therapeutic target in osteosarcoma.
Insights
L3MBTL2 suppresses osteosarcoma by regulating IFIT2. The UBE2O/L3MBTL2 pathway impacts tumor growth, offering a new therapeutic target for osteosarcoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Osteosarcoma is an aggressive bone cancer with limited effective treatments.
- Identifying novel therapeutic targets is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the role of L3MBTL2 in osteosarcoma.
- To explore the UBE2O/L3MBTL2 axis as a potential therapeutic strategy.
Main Methods:
- Investigated L3MBTL2's tumor suppressor function via transcriptional repression of IFIT2.
- Examined the formation of L3MBTL2-induced condensates involving Polycomb repressive complex 1.6.
- Analyzed the role of UBE2O in L3MBTL2 degradation and its impact on osteosarcoma growth.
- Correlated L3MBTL2 and UBE2O levels with patient prognosis.
- Assessed the effect of arsenic trioxide on the UBE2O/L3MBTL2 axis and osteosarcoma growth.
Main Results:
- L3MBTL2 acts as a tumor suppressor in osteosarcoma by repressing IFIT2 transcription.
- L3MBTL2 recruits Polycomb repressive complex 1.6 to form functional condensates essential for tumor suppression.
- UBE2O-mediated multi-monoubiquitination leads to L3MBTL2 proteasomal degradation, promoting osteosarcoma growth.
- A reverse correlation exists between L3MBTL2 and UBE2O in osteosarcoma tissues, with high UBE2O/low L3MBTL2 predicting poor prognosis.
- Arsenic trioxide treatment inhibits UBE2O, enhancing L3MBTL2 condensates and suppressing tumor growth.
Conclusions:
- L3MBTL2-induced condensates play a critical role in osteosarcoma tumor suppression.
- The UBE2O/L3MBTL2 axis is a key regulator of osteosarcoma progression.
- Targeting the UBE2O-L3MBTL2 interaction presents a promising therapeutic avenue for osteosarcoma.
