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Published on: August 5, 2022
KDM7B-mediated demethylation of RNF113A regulates small cell lung cancer sensitivity to alkylation damage
Tanveer Ahmad1, Xiaojie Yang2, Anne-Emmanuelle Foucher3
1Grenoble Alpes University, INSERM U1209, CNRS UMR 5309, Institut pour l'Avancée des Biosciences (IAB), ProMeDy, 38000 GRENOBLE, France.
Abstract:
Chemoresistance remains a major obstacle to effective cancer treatment, often driven by enhanced DNA repair mechanisms that enable tumor cells to withstand genotoxic therapies. One such pathway involves the atypical DNA damage repair complex ALKBH3-ASCC, activated by the E3 ligase RNF113A in response to alkylation damage. We previously showed that SMYD3-dependent methylation of RNF113A stimulates this pathway, enhancing DNA repair and promoting resistance. Here, we identify KDM7B/PHF8 as the bona fide RNF113A demethylase, establishing one of the first functional examples of a dynamic, reversible non-histone methylation event regulating genome integrity. KDM7B antagonizes SMYD3 activity by maintaining low levels of methylated RNF113A, thereby limiting ASCC activation and sensitizing cancer cells to alkylating agents. To dissect this regulation in depth, we focused on small cell lung cancer (SCLC), a particularly aggressive malignancy characterized by limited therapeutic options and rapid acquisition of resistance. In SCLC, high KDM7B levels correlate with improved patient prognosis, whereas xenografts with reduced expression exhibit diminished responses to alkylating treatment. Moreover, CRISPR-based on/off modulation of KDM7B in genetically engineered SCLC mouse models demonstrates its central role in determining tumor response to chemotherapy. Our findings position the RNF113A-ASCC axis as a central modulator of chemoresistance, regulated through a post-translational methylation switch representing an innovative therapeutic vulnerability that could be exploited to enhance the efficacy of alkylating agents. Targeting this pathway may provide new opportunities to overcome chemoresistance, with KDM7B levels serving as a predictive biomarker to guide treatment in SCLC.
Insights
Researchers discovered KDM7B demethylase reverses RNF113A methylation, controlling DNA repair and chemoresistance. This finding offers a new therapeutic target and biomarker for small cell lung cancer treatment.
Area of Science:
- Molecular Biology
- Cancer Research
- Epigenetics
Background:
- Chemoresistance is a major challenge in cancer therapy, often linked to enhanced DNA repair pathways.
- The atypical DNA damage repair complex ALKBH3-ASCC, activated by RNF113A, promotes resistance to genotoxic therapies.
- Previous work implicated SMYD3-dependent methylation of RNF113A in stimulating this resistance pathway.
Purpose of the Study:
- To identify the enzyme responsible for demethylating RNF113A, thereby regulating the DNA repair pathway.
- To investigate the role of this demethylation in controlling chemoresistance, particularly in small cell lung cancer (SCLC).
- To explore the therapeutic potential of targeting this regulatory axis.
Main Methods:
- Identification of KDM7B/PHF8 as the specific RNF113A demethylase.
- Analysis of RNF113A methylation dynamics and its impact on ASCC complex activation.
- In vivo studies using SCLC patient data, xenografts, and genetically engineered mouse models with CRISPR-based modulation of KDM7B.
- Correlation of KDM7B expression with patient prognosis and treatment response.
Main Results:
- KDM7B was identified as the bona fide demethylase of RNF113A, antagonizing SMYD3-mediated methylation.
- This reversible methylation switch dynamically regulates the activation of the RNF113A-ASCC DNA repair complex.
- Reduced KDM7B expression in SCLC models led to increased RNF113A methylation, heightened ASCC activity, and diminished response to alkylating agents.
- High KDM7B levels in SCLC patients correlated with better prognosis and sensitivity to chemotherapy.
Conclusions:
- The RNF113A-ASCC axis is a key regulator of chemoresistance, controlled by a reversible post-translational methylation event.
- KDM7B acts as a crucial tumor suppressor by limiting DNA repair and sensitizing cancer cells to alkylating agents.
- KDM7B represents a novel therapeutic vulnerability and its expression level can serve as a predictive biomarker for SCLC treatment strategies.
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