U.K. researchers: Blocking ‘rogue’ gene could stop the spread of most cancers
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NORWICH, U.K.—Scientists at the University of East Anglia (UEA) say they have discovered a "rogue" gene which, if blocked by the right drugs, could stop cancer in its tracks.
Published Jan. 24 by the journal Oncogene, the discovery is a breakthrough in the understanding of how cancer spreads, according to the researchers, who hope their findings will lead to new drugs that halt the critical late stage of the disease when cancer cells spread to other parts of the body.
The initial discovery was made while researchers were studying a group of natural cancer cell inhibitors called "Smads." The culprit gene, known as WWP2, is an enzymic bonding agent found inside cancer cells. It attacks and breaks down a natural inhibitor in the body that normally prevents cancer cells from spreading.
The UEA team found that by blocking WWP2, levels of the natural inhibitor are boosted and the cancer cells remain dormant. If a drug was developed that deactivated WWP2, conventional therapies and surgery could be used on primary tumors, with no risk of the disease taking hold elsewhere.
"In this study, we identify a HECT E3 ubiquitin ligase known as WWP2 (Full-length WWP2-FL), together with two WWP2 isoforms (N-terminal, WWP2-N; C-terminal WWP2-C), as novel Smad-binding partners," the researchers wrote. "We show that WWP2-FL interacts exclusively with Smad2, Smad3 and Smad7 in the TGFβ pathway. Interestingly, the WWP2-N isoform interacts with Smad2 and Smad3, whereas WWP2-C interacts only with Smad7. In addition, WWP2-FL and WWP2-C have a preference for Smad7 based on protein turnover and ubiquitination studies. Unexpectedly, we also find that WWP2-N, which lacks the HECT ubiquitin ligase domain, can also interact with WWP2-FL in a TGFβ-regulated manner and activate endogenous WWP2 ubiquitin ligase activity causing degradation of unstimulated Smad2 and Smad3. Consistent with our protein interaction data, overexpression and knockdown approaches reveal that WWP2 isoforms differentially modulate TGFβ-dependent transcription and EMT.
"Finally, we show that selective disruption of WWP2 interactions with inhibitory Smad7 can stabilize Smad7 protein levels and prevent TGFβ-induced EMT. Collectively, our data suggest that WWP2-N can stimulate WWP2-FL leading to increased activity against unstimulated Smad2 and Smad3, and that Smad7 is a preferred substrate for WWP2-FL and WWP2-C following prolonged TGFβ stimulation," the researchers concluded. "Significantly, this is the first report of an interdependent biological role for distinct HECT E3 ubiquitin ligase isoforms, and highlights an entirely novel regulatory paradigm that selectively limits the level of inhibitory and activating Smads."
Lead author Dr. Andrew Chantry of UEA's School of Biological Sciences, said in a statement issued by the university that the discovery could lead to the development of a new generation of drugs within the next decade that could be used to stop the aggressive spread of most forms of the disease, including breast, brain, colon and skin cancer.
"The late-stages of cancer involve a process known as metastasis, a critical phase in the progression of the disease that cannot currently be treated or prevented," said Chantry. "The challenge now is to identify a potent drug that will get inside cancer cells and destroy the activity of the rogue gene. This is a difficult, but not impossible task, made easier by the deeper understanding of the biological processes revealed in this study."
Dr. Surinder Soond, who spearheaded the experimental work in the laboratory, added: "This is a very novel and exciting approach to treating cancer and the spread of tumors which holds great potential."
The study, "Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signaling and EMT," was funded by U.K.-based charity the Association of International Cancer Research (AICR), with additional support from the Big C Charity and the British Skin Foundation.
Dr. Mark Matfield, scientific coordinator of AICR, said in a statement: "This is a very exciting new discovery and a perfect example of the way that basic research into cancer can open up ways to develop new ways to treat cancer."
Published Jan. 24 by the journal Oncogene, the discovery is a breakthrough in the understanding of how cancer spreads, according to the researchers, who hope their findings will lead to new drugs that halt the critical late stage of the disease when cancer cells spread to other parts of the body.
The initial discovery was made while researchers were studying a group of natural cancer cell inhibitors called "Smads." The culprit gene, known as WWP2, is an enzymic bonding agent found inside cancer cells. It attacks and breaks down a natural inhibitor in the body that normally prevents cancer cells from spreading.
The UEA team found that by blocking WWP2, levels of the natural inhibitor are boosted and the cancer cells remain dormant. If a drug was developed that deactivated WWP2, conventional therapies and surgery could be used on primary tumors, with no risk of the disease taking hold elsewhere.
"In this study, we identify a HECT E3 ubiquitin ligase known as WWP2 (Full-length WWP2-FL), together with two WWP2 isoforms (N-terminal, WWP2-N; C-terminal WWP2-C), as novel Smad-binding partners," the researchers wrote. "We show that WWP2-FL interacts exclusively with Smad2, Smad3 and Smad7 in the TGFβ pathway. Interestingly, the WWP2-N isoform interacts with Smad2 and Smad3, whereas WWP2-C interacts only with Smad7. In addition, WWP2-FL and WWP2-C have a preference for Smad7 based on protein turnover and ubiquitination studies. Unexpectedly, we also find that WWP2-N, which lacks the HECT ubiquitin ligase domain, can also interact with WWP2-FL in a TGFβ-regulated manner and activate endogenous WWP2 ubiquitin ligase activity causing degradation of unstimulated Smad2 and Smad3. Consistent with our protein interaction data, overexpression and knockdown approaches reveal that WWP2 isoforms differentially modulate TGFβ-dependent transcription and EMT.
"Finally, we show that selective disruption of WWP2 interactions with inhibitory Smad7 can stabilize Smad7 protein levels and prevent TGFβ-induced EMT. Collectively, our data suggest that WWP2-N can stimulate WWP2-FL leading to increased activity against unstimulated Smad2 and Smad3, and that Smad7 is a preferred substrate for WWP2-FL and WWP2-C following prolonged TGFβ stimulation," the researchers concluded. "Significantly, this is the first report of an interdependent biological role for distinct HECT E3 ubiquitin ligase isoforms, and highlights an entirely novel regulatory paradigm that selectively limits the level of inhibitory and activating Smads."
Lead author Dr. Andrew Chantry of UEA's School of Biological Sciences, said in a statement issued by the university that the discovery could lead to the development of a new generation of drugs within the next decade that could be used to stop the aggressive spread of most forms of the disease, including breast, brain, colon and skin cancer.
"The late-stages of cancer involve a process known as metastasis, a critical phase in the progression of the disease that cannot currently be treated or prevented," said Chantry. "The challenge now is to identify a potent drug that will get inside cancer cells and destroy the activity of the rogue gene. This is a difficult, but not impossible task, made easier by the deeper understanding of the biological processes revealed in this study."
Dr. Surinder Soond, who spearheaded the experimental work in the laboratory, added: "This is a very novel and exciting approach to treating cancer and the spread of tumors which holds great potential."
The study, "Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signaling and EMT," was funded by U.K.-based charity the Association of International Cancer Research (AICR), with additional support from the Big C Charity and the British Skin Foundation.
Dr. Mark Matfield, scientific coordinator of AICR, said in a statement: "This is a very exciting new discovery and a perfect example of the way that basic research into cancer can open up ways to develop new ways to treat cancer."
