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Updated: May 23, 2025
Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
Published on: April 26, 2017
Harnessing transcriptional regulation of alternative end-joining to predict cancer treatment
Roderic Espín1,2, Ferran Medina-Jover1,2,3, Javier Sigüenza-Andrade1,2
1ProCURE, Catalan Institute of Oncology, L'Hospitalet del Llobregat, Barcelona 08908, Spain.
Abstract:
Alternative end-joining (alt-EJ) is an error-prone DNA repair pathway that cancer cells deficient in homologous recombination rely on, making them vulnerable to synthetic lethality via inhibition of poly(ADP-ribose) polymerase (PARP). Targeting alt-EJ effector DNA polymerase theta (POLθ), which synergizes with PARP inhibitors and can overcome resistance, is of significant preclinical and clinical interest. However, the transcriptional regulation of alt-EJ and its interactions with processes driving cancer progression remain poorly understood. Here, we show that alt-EJ is suppressed by hypoxia while positively associated with MYC (myelocytomatosis oncogene) transcriptional activity. Hypoxia reduces PARP1 and POLQ expression, decreases MYC binding at their promoters, and lowers PARylation and alt-EJ-mediated DNA repair in cancer cells. Tumors with HIF1A mutations overexpress the alt-EJ gene signature. Inhibition of hypoxia-inducible factor 1α or HIF1A expression depletion, combined with PARP or POLθ inhibition, synergistically reduces the colony-forming capacity of cancer cells. Deep learning reveals the anticorrelation between alt-EJ and hypoxia across regions in tumor images, and the predictions for these and MYC activity achieve area under the curve values between 0.70 and 0.86. These findings further highlight the critical role of hypoxia in modulating DNA repair and present a strategy for predicting and improving outcomes centered on targeting alt-EJ.
Insights
Hypoxia suppresses alternative end-joining (alt-EJ) DNA repair, crucial for cancer cells. Targeting alt-EJ with PARP or POLθ inhibitors, especially in hypoxic tumors, offers a promising cancer treatment strategy.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- Alternative end-joining (alt-EJ) is an error-prone DNA repair pathway exploited by cancer cells lacking homologous recombination.
- Poly(ADP-ribose) polymerase (PARP) inhibitors create synthetic lethality in these cancers, with DNA polymerase theta (POLθ) showing synergistic potential.
Purpose of the Study:
- To investigate the transcriptional regulation of alt-EJ and its relationship with cancer progression.
- To explore the impact of hypoxia on alt-EJ and its therapeutic implications.
Main Methods:
- Analysis of alt-EJ gene expression in relation to hypoxia and MYC activity.
- Assessment of PARP1 and POLQ expression and MYC binding under hypoxic conditions.
- Evaluation of synergistic effects of inhibiting hypoxia-inducible factor 1α (HIF1A), PARP, or POLθ on cancer cell viability.
- Application of deep learning to tumor images to correlate alt-EJ and hypoxia.
Main Results:
- Hypoxia suppresses alt-EJ, reducing PARP1 and POLQ expression and MYC binding.
- Cancer cells with HIF1A mutations exhibit overexpression of the alt-EJ gene signature.
- Combined inhibition of HIF1A/hypoxia with PARP or POLθ inhibitors synergistically reduces cancer cell colony formation.
- Deep learning models accurately predict the anticorrelation between alt-EJ and hypoxia in tumor images.
Conclusions:
- Hypoxia plays a critical role in modulating DNA repair pathways like alt-EJ.
- Targeting alt-EJ in the context of tumor hypoxia presents a viable strategy for cancer therapy.
- This research provides a framework for predicting treatment outcomes based on hypoxia and alt-EJ activity.
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