CBX7 suppresses urinary bladder cancer progression via modulating AKR1B10-ERK signaling
Zhengnan Huang1, Yilin Yan1, Zhen Zhu2
1Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 200080, Shanghai, China.
Abstract:
The chromobox (CBX) proteins mediate epigenetic gene silencing and have been implicated in the cancer development. By analyzing eight CBX family members in TCGA dataset, we found that chromobox 7 (CBX7) was the most strikingly downregulated CBX family member in urinary bladder cancer (UBC), as compared to normal tissues. Though dysregulation of CBX7 has been reported in multiple cancers, its specific role and clinical relevance in UBC remain unclear. Herein, we found that frequent downregulation of CBX7 in UBC specimens, which was due to its promoter hypermethylation, was correlated with poor prognosis. The ectopic expression of CBX7 suppressed UBC cell proliferation, migration, invasion, and cancer stemness, whereas CBX7 depletion promoted cancer cell aggressiveness. Importantly, CBX7 overexpression in UBC cells inhibited tumorigenicity, whereas CBX7 depletion promoted the tumor development, indicating its tumor-suppressive role in UBC. Using RNA-seq and chromosome immunoprecipitation (ChIP) assays, we identified aldo-keto reductase family 1 member 10 (AKR1B10) as a novel downstream target of CBX7, which was negatively modulated by CBX7 in a PRC1-dependent manner and involved in stimulating ERK signaling. Consistently, AKR1B10 overexpression induced cancer cell aggressiveness, whereas suppression of AKR1B10 by siRNA or its small molecular inhibitor, oleanolic acid, reversed the CBX7 deficiency-induced cellular effects. AKR1B10 overexpression was negatively associated with CBX7 downregulation and predicted poor clinical outcomes in UBC patients. Taken together, our results indicate that CBX7 functions as a tumor suppressor to downregulate AKR1B10 and further inactivates ERK signaling. This CBX7/AKR1B10/ERK signaling axis may provide a new therapeutic strategy against UBC.
Insights
Chromobox 7 (CBX7) acts as a tumor suppressor in urinary bladder cancer (UBC). Its downregulation, due to promoter hypermethylation, promotes UBC progression by upregulating AKR1B10 and activating ERK signaling.
Area of Science:
- Epigenetics
- Oncology
- Molecular Biology
Background:
- Chromobox (CBX) proteins are involved in epigenetic gene silencing and cancer development.
- Chromobox 7 (CBX7) is notably downregulated in urinary bladder cancer (UBC) compared to normal tissues.
- The specific role and clinical significance of CBX7 in UBC are not well understood.
Purpose of the Study:
- To investigate the role and clinical relevance of CBX7 in UBC.
- To identify downstream targets and signaling pathways regulated by CBX7 in UBC.
- To explore the potential of the CBX7/AKR1B10/ERK axis as a therapeutic strategy for UBC.
Main Methods:
- Analysis of TCGA dataset for CBX family member expression in UBC.
- Investigation of CBX7 promoter methylation in UBC specimens.
- Functional assays including cell proliferation, migration, invasion, stemness, and tumorigenicity.
- RNA-sequencing (RNA-seq) and Chromosome Immunoprecipitation (ChIP) assays.
- Assessment of aldo-keto reductase family 1 member 10 (AKR1B10) expression and its modulation by CBX7 and ERK signaling.
Main Results:
- CBX7 is frequently downregulated in UBC due to promoter hypermethylation, correlating with poor prognosis.
- CBX7 overexpression suppresses UBC cell proliferation, migration, invasion, and stemness, while CBX7 depletion promotes aggressiveness.
- CBX7 inhibits tumorigenicity in UBC, confirming its tumor-suppressive role.
- AKR1B10 is identified as a novel downstream target of CBX7, negatively regulated via PRC1 and involved in ERK signaling activation.
- AKR1B10 overexpression promotes UBC cell aggressiveness, and its inhibition reverses CBX7 deficiency effects.
- AKR1B10 overexpression is associated with CBX7 downregulation and predicts poor outcomes in UBC patients.
Conclusions:
- CBX7 functions as a tumor suppressor in UBC by downregulating AKR1B10 and inhibiting ERK signaling.
- The CBX7/AKR1B10/ERK signaling axis represents a potential therapeutic target for UBC.
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