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MiR-766 induces p53 accumulation and G2/M arrest by directly targeting MDM4
Qingqing Wang1, Luke A Selth2,3, David F Callen1
1Breast Cancer Genetics Group, Centre for Personalised Cancer Medicine, School of Medicine, University of Adelaide, South Australia.
Abstract:
p53, a transcription factor that participates in multiple cellular functions, is considered the most important tumor suppressor. Previous evidence suggests that post-transcriptional deregulation of p53 by microRNAs contributes to tumorigenesis, tumor progression and therapeutic resistance. In the present study, we found that the microRNA miR-766 was aberrantly expressed in breast cancer, and that over-expression of miR-766 caused accumulation of wild-type p53 protein in multiple cancer cell lines. Supporting its role in the p53 signalling pathway, miR-766 decreased cell proliferation and colony formation in several cancer cell lines, and cell cycle analyses revealed that miR-766 causes G2 arrest. At a mechanistic level, we demonstrate that miR-766 enhances p53 signalling by directly targeting MDM4, an oncogene and negative regulator of p53. Analysis of clinical genomic data from multiple cancer types supports the relevance of miR-766 in p53 signalling. Collectively, our study demonstrates that miR-766 can function as a novel tumor suppressor by enhancing p53 signalling.
Insights
MicroRNA miR-766 acts as a tumor suppressor by enhancing p53 signaling. It targets MDM4, leading to p53 accumulation, cell cycle arrest, and reduced proliferation in cancer cells.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- p53 is a critical tumor suppressor involved in cellular functions.
- MicroRNA deregulation of p53 is linked to cancer development and treatment resistance.
Purpose of the Study:
- Investigate the role of miR-766 in breast cancer.
- Determine if miR-766 influences p53 signaling and tumor suppression.
Main Methods:
- Assessed miR-766 expression in breast cancer.
- Overexpressed miR-766 in cancer cell lines to observe p53 protein levels.
- Performed cell proliferation, colony formation, and cell cycle analyses.
- Identified MDM4 as a direct target of miR-766 using mechanistic studies.
- Analyzed clinical genomic data for miR-766 relevance in p53 signaling.
Main Results:
- miR-766 was aberrantly expressed in breast cancer.
- Overexpression of miR-766 led to wild-type p53 protein accumulation.
- miR-766 reduced cancer cell proliferation and colony formation.
- miR-766 induced G2 cell cycle arrest.
- miR-766 directly targets and inhibits MDM4, a negative regulator of p53.
- Clinical data confirmed miR-766's role in p53 signaling across multiple cancer types.
Conclusions:
- miR-766 functions as a novel tumor suppressor.
- Enhancement of p53 signaling by miR-766 offers a new therapeutic avenue.