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ATM Paradoxically Promotes Oncogenic Transformation via Transcriptional Reprogramming
Xinjian Liu1,2, Mengjie Hu3, Pei Liu2
1Department of Dermatology, Duke University Medical Center, Durham, North Carolina. chuan.li@duke.edu jnulxj@163.com.
Cancer Research
|February 16, 2020
Summary
The ataxia-telangiectasia-mutated (ATM) gene unexpectedly promotes cancer by reprogramming cell transcription. ATM deficiency or inhibition reduces cancer stem cell formation and tumorigenesis, revealing a novel pro-oncogenic role.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The role of the ataxia-telangiectasia-mutated (ATM) gene in human malignancies is not fully understood, particularly in solid tumors.
- ATM is a key regulator of the DNA damage response, traditionally viewed as a tumor suppressor.
Purpose of the Study:
- To investigate the involvement of ATM in the transformation of primary human cells into cancer stem cells.
- To elucidate the mechanism by which ATM influences oncogene-induced malignant transformation.
Main Methods:
- Exogenous expression of an oncogene cocktail in human fibroblasts.
- Assessment of DNA double-strand breaks and ATM activation.
- Analysis of transcriptional reprogramming and chromatin structure.
- Evaluation of ATM deficiency and inhibition on cell transformation and tumorigenesis in mouse models.
Main Results:
- Oncogene expression induced DNA double-strand breaks, leading to persistent ATM activation.
- Activated ATM facilitated global transcriptional reprogramming via chromatin relaxation, enabling oncogenic transcription factor access.
- ATM deficiency significantly attenuated oncogene-induced cell transformation.
- ATM inhibition reduced mammary cancer tumorigenesis in a mouse model.
Conclusions:
- ATM plays a novel pro-oncogenic role in facilitating oncogene-induced malignant transformation through transcriptional reprogramming.
- Contrary to established theory, ATM can promote rather than suppress tumorigenesis, depending on the cellular context.
- ATM and the DNA damage response have a previously unrecognized function in promoting mammalian cell transformation.
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