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o8G-modified circPLCE1 inhibits lung cancer progression via chaperone-mediated autophagy

Qingyun Zhao^1,2, Dunyu Cai^1,2, Haotian Xu^1,2

¹School of Public Health, Guangxi Medical University, Nanning, 530021, China.

Molecular Cancer

|March 18, 2025

Abstract

Background:

Lung cancer poses a serious threat to human health, but its molecular mechanisms remain unclear. Circular RNAs (circRNAs) are closely associated with tumour progression, and the important role of 8-oxoguanine (o8G) modification in regulating the fate of RNA has been gradually revealed. However, o8G modification of circRNAs has not been reported. We identified circPLCE1, which is significantly downregulated in lung cancer, and further investigated the o8G modification of circPLCE1 and the related mechanism in lung cancer progression.

Methods:

We identified differentially expressed circRNAs by RNA high-throughput sequencing and then conducted methylated RNA immunoprecipitation (MeRIP), immunofluorescence (IF) analysis, crosslinking immunoprecipitation (CLIP) and actinomycin D (ActD) assays to explore circPLCE1 o8G modification. The biological functions of circPLCE1 in vivo and in vitro were clarified via establishing a circPLCE1 silencing/overexpression system. Tagged RNA affinity purification (TRAP), RNA Immunoprecipitation (RIP) and coimmunoprecipitation (Co-IP) assays, and pSIN-PAmCherry-KFERQ-NE reporter gene were used to elucidate the molecular mechanism by which circPLCE1 inhibits lung cancer progression.

Results:

This study revealed that reactive oxygen species (ROS) can induce circPLCE1 o8G modification and that AUF1 can mediate a decrease in circPLCE1 stability. We found that circPLCE1 significantly inhibited lung cancer progression in vitro and in vivo and that its expression was associated with tumour stage and prognosis. The molecular mechanism was elucidated: circPLCE1 targets the HSC70 protein, increases its ubiquitination level, regulates ATG5-dependent macroautophagy via the chaperone-mediated autophagy (CMA) pathway, and ultimately inhibits lung cancer progression.

Conclusion:

o8G-modified circPLCE1 inhibits lung cancer progression through CMA to inhibit macroautophagy and alter cell fate. This study provides not only a new theoretical basis for elucidating the molecular mechanism of lung cancer progression but also potential targets for lung cancer treatment.

Insights

8-oxoguanine (o8G) modified circPLCE1 inhibits lung cancer progression by regulating chaperone-mediated autophagy (CMA). This discovery offers new insights into lung cancer mechanisms and potential therapeutic targets.

Area of Science:

Molecular Biology
Cancer Research
RNA Biology

Background:

Lung cancer remains a significant health concern with unclear molecular underpinnings.
Circular RNAs (circRNAs) are implicated in tumor progression, and 8-oxoguanine (o8G) modification influences RNA fate.
The o8G modification of circRNAs and its role in lung cancer were previously unreported.

Purpose of the Study:

To identify and characterize circPLCE1, a circRNA downregulated in lung cancer.
To investigate the o8G modification of circPLCE1 and its mechanistic role in lung cancer progression.
To elucidate how circPLCE1, upon o8G modification, impacts lung cancer cell fate and tumor growth.

Main Methods:

RNA high-throughput sequencing to identify differentially expressed circRNAs.
Methylated RNA immunoprecipitation (MeRIP), immunofluorescence (IF), and crosslinking immunoprecipitation (CLIP) to study circPLCE1 o8G modification.
In vitro and in vivo functional assays, including silencing/overexpression systems, TRAP, RIP, Co-IP, and reporter gene assays to explore the molecular mechanism.

Main Results:

Reactive oxygen species (ROS) induce o8G modification in circPLCE1, and AUF1 decreases its stability.
circPLCE1 significantly inhibits lung cancer progression both in vitro and in vivo, with expression correlating with tumor stage and prognosis.
circPLCE1 targets HSC70, increasing its ubiquitination and regulating ATG5-dependent macroautophagy via the chaperone-mediated autophagy (CMA) pathway.

Conclusions:

o8G-modified circPLCE1 inhibits lung cancer progression by suppressing macroautophagy through the CMA pathway, thereby altering cell fate.
This study establishes a novel theoretical framework for understanding lung cancer progression mechanisms.
The findings identify o8G-modified circPLCE1 and its associated pathway as potential therapeutic targets for lung cancer treatment.

Read full analysis

Keywords:

CircRNA HSC70 Lung cancer Molecular chaperone-mediated autophagy O8G modification

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