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Updated: Jan 21, 2026
Modeling Breast Cancer in Human Breast Tissue using a Microphysiological System
Published on: April 23, 2021
Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer
Laia Piqué1, Alexia Martinez de Paz1, David Piñeyro1
1Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
Abstract:
Human tumors show altered patterns of protein isoforms that can be related to the dysregulation of messenger RNA alternative splicing also observed in transformed cells. Although somatic mutations in core spliceosome components and their associated factors have been described in some cases, almost nothing is known about the contribution of distorted epigenetic patterns to aberrant splicing. Herein, we show that the splicing RNA-binding protein CELF2 is targeted by promoter hypermethylation-associated transcriptional silencing in human cancer. Focusing on the context of breast cancer, we also demonstrate that CELF2 restoration has growth-inhibitory effects and that its epigenetic loss induces an aberrant downstream pattern of alternative splicing, affecting key genes in breast cancer biology such as the autophagy factor ULK1 and the apoptotic protein CARD10. Furthermore, the presence of CELF2 hypermethylation in the clinical setting is associated with shorter overall survival of the breast cancer patients carrying this epigenetic lesion.
Insights
Epigenetic silencing of the splicing factor CELF2 via promoter hypermethylation contributes to breast cancer progression. Restoring CELF2 inhibits tumor growth and corrects aberrant splicing of key cancer-related genes, with CELF2 hypermethylation predicting poor patient survival.
Area of Science:
- Molecular Biology
- Cancer Biology
- Epigenetics
Background:
- Altered protein isoforms in human tumors are linked to dysregulated messenger RNA (mRNA) alternative splicing.
- While somatic mutations in spliceosome components are known, the role of epigenetic changes in aberrant splicing remains largely unexplored.
Purpose of the Study:
- To investigate the contribution of epigenetic alterations to aberrant splicing in human cancer.
- To examine the role of the splicing factor CELF2 in breast cancer, focusing on its epigenetic regulation and functional impact.
Main Methods:
- Analysis of CELF2 promoter methylation in human cancer, specifically breast cancer.
- Assessment of CELF2 restoration effects on cancer cell growth.
- Investigation of downstream alternative splicing patterns upon CELF2 loss.
- Correlation of CELF2 hypermethylation with patient survival data.
Main Results:
- CELF2 is targeted by promoter hypermethylation leading to transcriptional silencing in human cancer.
- Restoration of CELF2 exhibits growth-inhibitory effects in breast cancer models.
- Epigenetic loss of CELF2 results in aberrant alternative splicing of critical genes like ULK1 and CARD10.
- Clinical analysis shows CELF2 hypermethylation is associated with shorter overall survival in breast cancer patients.
Conclusions:
- Promoter hypermethylation and subsequent silencing of CELF2 is a significant epigenetic event in human cancer, particularly breast cancer.
- CELF2 acts as a tumor suppressor in breast cancer by regulating alternative splicing of key oncogenic and tumor suppressor pathways.
- CELF2 hypermethylation serves as a potential prognostic biomarker for breast cancer patients.
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