Researchers find enzyme that cleans cells of cancer gene

Researchers at the University of Manchester and the University of Buffalo have discovered an enzyme that “cleans” cells of WT1, a gene that is believed to be responsible for a wide range of cancers

Amy Swinderman
MANCHESTER, England—Researchers at the University of Manchester and the University of Buffalo have discovered an enzyme that "cleans" cells of WT1, a gene that is believed to be responsible for a wide range of cancers. According to the researchers, their work may pave the way for the development of treatments for cancers in which WT1 expression is elevated.

The finding, published in late January in the Cell Press journal Molecular Cell, identified the serine protease HtrA2 as a WT1 binding partner and found that it cleaves WT1 at multiple sites following the treatment of cells with cytotoxic drugs. Ablation of HtrA2 activity, either by chemical inhibitor or by the use of small interfering RNA, prevents the proteolysis of WT1 under apoptotic conditions. Moreover, the apoptosis-dependent cleavage of WT1 is defective in HtrA2 knockout cells. Proteolysis of WT1 by HtrA2 causes the removal of WT1 from its binding sites at gene promoters, leading to alterations in gene regulation that enhance apoptosis, according to researchers Drs. Joerg Hartkamp and Stefan Roberts.

"Our findings provide insights into the function of HtrA2 in the regulation of apoptosis and the oncogenic activities of WT1," the study concludes.

Previous research on WT1 has shown that it suppresses the development of Wilms' tumor of the kidney, a rare cancer that affects one in 10,000 children. However, it has a cancer-causing role in other forms of the disease, particularly leukemias such as acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). In addition, high expression of WT1 is associated with a bad prognosis in AML patients, while trials using peptide vaccines against WT1 in patients with lung cancer, breast cancer and leukemia were promising.

WT1 target genes include growth factors, differentiation markers, cell-cycle regulators and apoptosis regulators. The transcriptional regulatory properties of WT1 are complex, and it elicits both activator and repressor functions. How WT1 manifests these distinct activities is not clear, but several binding partners of WT1 have been proposed to regulate its function.

This study is the first to identify the enzyme that can rid cells of WT1. The researchers identified the serine protease HtrA2 as a WT1-interacting protein and demonstrated that it can degrade WT1. Thus, they conclude that the aberrant expression of WT1 plays a critical role in either or both the transformation process and the maintenance of the transformed phenotype. HtrA2-mediated proteolysis of WT1 might, therefore, directly contribute to the effect of chemotherapeutic drugs in the treatment of WT1-dependent tumors, they say.


"We show that endogenous WT1 in tumor cells is cleaved following cytotoxic drug treatment and demonstrate that this cleavage is HtrA2 dependent," the researchers stated. "Our findings suggest that HtrA2 is a critical regulator of WT1 under proapoptotic conditions. When WT1 acts as an oncogene, the activation of HtrA2 by proapoptotic stimuli and subsequent degradation of WT1 might facilitate the clearance of tumorigenic cells. Indeed, tumors that retain high expression of WT1 following chemotherapy generally result in a poor outcome. Moreover, clinical trials using peptide vaccines against WT1 in patients with leukemia, breast and lung cancer are showing promising therapeutic effects."

The researchers note that further investigation will be required to decipher the complex interplay of the WT1 target genes that are altered in expression following proteolysis of WT1.

"Further studies will determine how the processing of WT1 is regulated by WT1 cofactors and the role that they play in the modulation of WT1 activity in development and disease," they add.

The research team says it will study HtrA2 further to find out how it is inactivated in cancer cells and what other targets HtrA2 has. Eventually, these findings could help pharmaceutical companies design a drug to reactivate HtrA2 and apply the protease to different diseases.

The study, "The Wilms' Tumour Suppressor Protein WT1 is processed by the serine protease HtrA2/Omi," was funded by the American Institute for Cancer Research (AICR), Cancer Research UK and the Wellcome Trust.
 

Amy Swinderman

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