circPRMT10 regulated by QKI hypermethylation attenuates lung tumorigenesis induced by tobacco carcinogen NNK
Xietian Xiao1, Yadong Li2, Tianshu Lin3
1School of Public Health, Guangzhou Medical University, Guangzhou 511436, China; State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
Abstract:
Chronic exposure to environmental carcinogens is a major cause of tumorigenesis. A potent tobacco-specific nitrosamine carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), exhibits high carcinogenicity to induce lung cancer. However, the function and mechanism of circular RNA (circRNA) in chemical carcinogenesis, especially the regulation of circRNA formation upon exposure to environmental chemicals, remain unclear. This study identified that circPRMT10 (hsa_circ_0009048) was downregulated in NNK-exposed human bronchial epithelial cells (16HBE and BEAS-2B). Additionally, the RNA-binding protein Quaking (QKI) was responsible for the biogenesis of circPRMT10 through its binding interaction with the flanking introns of circPRMT10. Moreover, NNK exposure resulted in hypermethylation of the QKI promoter, leading to QKI downregulation, which ultimately affected circPRMT10 formation. Using a cell model of chronic exposure to low-dose NNK, we found that overexpression of circPRMT10 significantly inhibited NNK-induced lung carcinogenesis by suppressing cell proliferation, cell cycle progression, and xenograft tumor growth. Finally, moesin (MSN) was identified as a downstream target of circPRMT10 via RNA pull-down and western blot assays and demonstrated a potential role in the regulation of lung cancer development. In conclusion, our findings reveal the underlying mechanisms of circRNA biogenesis following exposure to chemical carcinogens, providing novel insights into the role of circRNAs in chemical carcinogenesis.
Insights
Environmental carcinogen NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) exposure downregulates circPRMT10, a circular RNA that inhibits lung cancer development by targeting moesin (MSN). This study clarifies circRNA regulation in chemical carcinogenesis.
Area of Science:
- Molecular Biology
- Cancer Research
- Environmental Health
Background:
- Chronic exposure to environmental carcinogens like NNK is a key driver of cancer.
- The role of circular RNAs (circRNAs) in chemical carcinogenesis and their regulatory mechanisms remain largely unknown.
- Understanding circRNA regulation is crucial for developing novel cancer prevention and treatment strategies.
Purpose of the Study:
- To investigate the role and regulatory mechanisms of circRNAs in NNK-induced lung carcinogenesis.
- To identify specific circRNAs and their associated proteins involved in the cellular response to NNK exposure.
- To elucidate the functional impact of circPRMT10 on lung cancer development and identify its downstream targets.
Main Methods:
- NNK exposure models using human bronchial epithelial cells (16HBE, BEAS-2B).
- RNA immunoprecipitation, promoter methylation analysis, and RNA pull-down assays to identify regulatory interactions.
- Cellular and xenograft models to assess the functional role of circPRMT10 in lung carcinogenesis.
- Western blot analysis to confirm protein targets.
Main Results:
- circPRMT10 was found to be downregulated in NNK-exposed cells.
- The RNA-binding protein Quaking (QKI) was identified as a key regulator of circPRMT10 biogenesis.
- NNK exposure led to QKI downregulation via promoter hypermethylation, impacting circPRMT10 levels.
- Overexpression of circPRMT10 suppressed NNK-induced lung cancer cell proliferation, cell cycle progression, and tumor growth.
- Moesin (MSN) was identified as a downstream target of circPRMT10.
Conclusions:
- This study reveals that NNK-induced hypermethylation of the QKI promoter downregulates QKI, subsequently affecting circPRMT10 formation and promoting lung carcinogenesis.
- circPRMT10 acts as a tumor suppressor in NNK-induced lung cancer by inhibiting proliferation and cell cycle progression, partly through targeting MSN.
- These findings provide novel insights into the mechanisms of circRNA regulation in chemical carcinogenesis and highlight circPRMT10 as a potential therapeutic target.
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