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Published on: August 2, 2024
BMAL2 is a druggable target for ovarian clear cell carcinoma (OCCC)
Grace Y T Tan1,2, Pei-Yi Lin2, Li-Tzu Cheng1,2
1Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and National Defense Medical University, Taipei, 11490, Taiwan.
Abstract:
Ovarian clear cell carcinomas (OCCC), particularly cases that retain wild-type AT-rich interactive domain 1 A (ARID1A) expression (approximately 50% of the OCCC cases), are chemoresistant and lack specific therapies. We identified BMAL2 as a critical OCCC oncogene that promotes tumorigenesis by preventing endogenous DNA damage. BMAL2 depletion altered the expression of genes encoding DNA damage repair proteins, including RAD51, a core enzyme of the homologous recombination (HR) pathway. This led to DNA double-stranded break accumulation, decreased cell viability and reduced tumor growth. This dependence on BMAL2 to maintain DNA integrity and cell viability can be a new route to suppress OCCC. Consistent with this idea, we found that GW833972A, a cannabinoid receptor agonist, bound BMAL2 with high affinity and facilitated its protein degradation. This in turn reduced RAD51 expression, leading to an accumulation of DNA damage, decreased cell viability and reduced OCCC tumor growth. GW833972A is effective by itself at high dose and can also be used at lower dosages to enhance the effectiveness of Poly (ADP-ribose) polymerase inhibitor (PARPi) treatments in BMAL2-expressing OCCC. Together, our findings reveal an essential oncogenic role of BMAL2 and demonstrate that it is an appealing therapeutic target, especially for ARID1A-wt OCCC.
Insights
BMAL2 is a critical oncogene in ovarian clear cell carcinomas (OCCC), promoting tumor growth by preventing DNA damage. Targeting BMAL2 with GW833972A offers a new therapeutic strategy for OCCC, especially in ARID1A-wild-type cases.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ovarian clear cell carcinomas (OCCC) with wild-type ARID1A are chemoresistant and lack targeted therapies.
- BMAL2 is identified as a key oncogene in OCCC, crucial for preventing endogenous DNA damage and maintaining tumor growth.
Purpose of the Study:
- To investigate the oncogenic role of BMAL2 in OCCC.
- To explore BMAL2 as a therapeutic target for OCCC, particularly ARID1A-wild-type cases.
Main Methods:
- Investigated BMAL2's role in DNA damage repair and OCCC tumorigenesis.
- Assessed the effect of BMAL2 depletion on DNA damage and cell viability.
- Evaluated GW833972A, a cannabinoid receptor agonist, for its ability to degrade BMAL2 and its therapeutic potential in OCCC models.
Main Results:
- BMAL2 depletion led to DNA double-stranded break accumulation and reduced OCCC cell viability and tumor growth.
- GW833972A induced BMAL2 protein degradation, decreased RAD51 expression, and inhibited OCCC tumor growth.
- GW833972A demonstrated efficacy as a monotherapy and enhanced Poly (ADP-ribose) polymerase inhibitor (PARPi) effectiveness in BMAL2-expressing OCCC.
Conclusions:
- BMAL2 plays an essential oncogenic role in OCCC by maintaining DNA integrity.
- Targeting BMAL2, particularly with GW833972A, represents a promising therapeutic strategy for OCCC, especially ARID1A-wild-type subtypes.
