One of several types of protein that can generate cells with stem cell-like properties that have the ability to form diverse types of tissue is “zinc finger E-box binding homeobox,” AKA ZEB1. Based on recent published research, scientists at the MD Anderson Cancer Center in Houston think ZEB1, conventionally believed to keep breast cancer cells from being successfully treated with radiation therapy, may actually be helping breast tumor cells repair DNA damage caused by radiation treatment by ramping up a first-line of defense known as DNA damage response pathway.
MD Anderson assistant professor of experimental radiation oncology Dr. Li Ma, Ph.D., and colleagues reported their findings in this month’s issue of Nature Cell Biology. The study, entitled ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1 (Nature Cell Biology, 2014; DOI: 10.1038/ncb3013) is coauthored by Peijing Zhang, Li Wang, Jinsong Zhang, Jingsong Yuan, Min Wang, Dahu Chen, Junjie Chen, and Li Ma of MD Anderson’s Department of Experimental Radiation Oncology; Yongkun Wei, Yutong Sun & Mien-Chie Hung of the department of Molecular and Cellular Oncology; Bisrat G. Debeb, Wendy A. Woodward and K. Kian Ang of the Department of Radiation Oncology; Yuan Yuan and Han Liang of the Department of Bioinformatics and Computational Biology; Yongqing Liu & Douglas C. Dean of the Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville Health Sciences Center, at Louisville, Kentucky; Ye Hu of the Department of Nanomedicine, Houston Methodist Research Institute; Mien-Chie Hung of the Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan. Mien-Chie Hung, Junjie Chen, and Li Ma are also associated with the Cancer Biology Program of the Graduate School of Biomedical Sciences at the University of Texas Health Science Center at Houston.
The coauthors note that Epithelialmesenchymal transition (EMT) is associated with characteristics of breast cancer stem cells, including chemoresistance and radioresistance, but it is unclear whether EMT itself or specific EMT regulators play causal roles in these properties.
The researchers identify an EMT-inducing transcription factor, the aforementioned ZEB1, as a regulator of radiosensitivity and DNA damage response. Radioresistant subpopulations of breast cancer cells derived from ionizing radiation exhibit hyperactivation of the kinase ATM and upregulation of ZEB1, and the latter promotes tumor cell radioresistance in vitro and in vivo.
Mechanistically, the coauthors say ATM phosphorylates and stabilizes ZEB1 in response to DNA damage. ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitylate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation. They conclude that these findings identify ZEB1 as an ATM substrate linking ATM to CHK1 and the mechanism underlying the association between EMT and radioresistance.
“Radiation therapy causes cell death by inducing DNA breaks,” says Dr. Ma. “The rationale for treating tumors with radiation without damaging normal tissues is that, compared with normal cells, tumor cells are actively dividing and often have defects in DNA damage repair machinery. Tumor cells are thus less able to repair DNA damage. But not always. Sometimes the body produces tumor cells resistant to radiation. They are somehow able to turn on the DNA damage response apparatus. Until now, the question has always been how?”
Dr. Ma’s team has demonstrated that the wily tumor cells’ ability to push the panic button at the last second can be triggered by ZEB1’s penchant for launching an operation that generates cancer stem cells.
The main goal of Dr. Ma’s laboratory and her team’s ongoing research is to better understand regulation of tumor invasion, metastasis, and epithelial-mesenchymal transition (EMT) by non-coding RNAs, and to develop novel therapeutic strategies. Metastasis, which is a multi-step process wherein primary tumor cells disseminate to other sites within the body and form secondary cancer tumors, is the primary cause of cancer death, and still remains one of the least understood pathological processes within the study of cancer. New metastatic disease biomarkers and effective targets for therapeutic intervention, which include proteins, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs), continue to be highly sought by researchers.
Dr. Ma’s team and others have demonstrated the existence of metastasis-promoting and metastasis-suppressing miRNAs. The molecular mechanisms by which these individual miRNAs function in metastatic progression warrant further investigation. Currently, her lab is working on four projects related to this topic: 1) dissecting the role of miR-10b in malignant progression using genetically engineered mouse models. 2) identifying the functional targets of metastasis-promoting miRNAs. 3) identifying and characterizing new epithelial-mesenchymal transition (EMT)-regulating miRNAs. 4) identifying lncRNAs that regulate EMT and metastasis. Collectively, the knowledge gained from these studies will fundamentally advance our current understanding of how miRNAs and lncRNAs regulate metastasis and EMT and may have important clinical implications.
“The cancer stem cells have been shown to promote radioresistance through activation of the DNA damage response system,” says Dr. Ma in an MD Anderson release. “Our studies have shown that ZEB1 can induce a process known as epithelial-mesenchymal transition (EMT) which allows certain tumor to acquire cancer stem cell properties including radioresistance. EMT is one way the body responds to wound healing and it is believed that cancer has found a method for using EMT to promote tumor progression. ZEB1 achieves this unfortunate result through a complex chain of events that permit a gene known as ATM to stabilize the protein Chk1 that plays an important role in DNA damage response. ZEB1 promotes Chk1s ability to allow tumor radioresistance through deployment of an enzyme called USP7.”
Dr. Ma says the hope is that new approaches to addressing radiation resistance may be developed through gaining better insight into how this signaling pathway keeps tumor cells growing despite being bombarded with toxic radiation treatments. “Radiation therapy plays a key role in breast cancer management, she observes. “To overcome the obstacle of radioresistant tumor cells, it is important to identify the critical causes and to develop safe and effective new methods for treatment including the possible use of agents that target ZEB1 and which inhibit CHK1.”
The study was funded by the National Institutes of Health (R00CA138572, R01CA166051, R01CA181029 and U54CA151668) and a Cancer Prevention Research Institute of Texas scholar award (R1004).
The University of Texas MD Anderson Cancer
Nature Cell Biology
The University of Texas MD Anderson Cancer