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Research Highlight | June 03, 2019

Terry Fox New Investigator publishes two major papers in top scientific journals

It has been a prolific quarter for Dr. Housheng Hansen He, a University Health Network researcher and TFRI New Investigator who focuses on prostate cancer: in the span of just a couple of months, his papers have been published in Cell and Nature Communications, two of the world’s biggest scientific journals.

In the Cell paper (February 2019), Dr. He and his team, which includes former New Investigator Dr. Paul Boutros (Ontario Institute for Cancer Research), describe, for the first time ever, the RNA circularization profile of a large number of prostate tumours.

By utilizing a novel sequencing method known as ultra-deep, non-poly-A RNA-seq the team was able to highlight the prevalence and importance of circular RNAs (circRNAs), a rarely studied RNA species, in prostate cancer.

According to Dr. He, circRNAs are increasingly becoming an object of study by researchers and more and more publications reveal that they may help code for certain proteins linked to cancer. In this context, mapping the circular RNA profile of prostate cancer tumours through the use of novel techniques, could help pinpoint the role they play in cancer development as well as identify new therapeutic targets.

“We showed that a substantial subset of circular RNAs (around 11% of what we screened) were important for driving cancer growth,” said Dr. He. “This provides numerous opportunities for developing new therapeutic targets and advocates attention to this special genetic material.”

Finding a new driver in neuroendocrine prostate cancer

Dr. He’s second paper, published in Nature Communications (January 2019), revealed that ONECUT2, a transcription factor that stimulates the expression of certain genes, works together with hypoxia to drive the development of a deadly type of prostate cancer known as neuroendocrine prostate cancer (NEPC).

“By using systematical bioinformatics analysis and mechanistic experiments, we proved ONECUT2-hypoxia axis is one of the most important driving mechanisms of NEPC,” Dr. He said. “Our finding suggests NEPC tumours are highly hypoxic and very sensitive to hypoxia-directed therapy, which may greatly improve the survival time of NEPC patients.”

The mechanisms identified by Dr. He and his team can be expanded to other small cell neuroendocrine tumours such as small cell lung cancers, as ONECUT2 is commonly upregulated in these types of tumours.

Cell Paper

Widespread and Functional RNA Circularization in Localized Prostate Cancer

Authors

Sujun Chen, Vincent Huang, Xin Xu, Julie Livingstone, Fraser Soares, Jouhyun Jeon, Yong Zeng, Junjie Tony Hua, Jessica Petricca, Haiyang Guo, Miranda Wang, Fouad Yousif, Yuzhe Zhang, Nilgun Donmez, Musaddeque Ahmed, Stas Volik, Anna Lapuk, Melvin L.K. Chua, Lawrence E. Heisler, Adrien Foucal, Natalie S. Fox, Michael Fraser, Vinayak Bhandari, Yu-Jia Shiah, Jiansheng Guan,  Jixi Li, Michele Orain,Valerie Picard, Helene Hovington, Alain Bergeron, Louis Lacombe, Yves Fradet, Bernard Tetu, Stanley Liu, Felix Feng, Xue Wu, Yang W. Shao, Malgorzata A. Komor, Cenk Sahinalp, Colin Collins, Youri Hoogstrate, Mark de Jong, Remond J.A. Fijneman, Teng Fei, Guido Jenster, Theodorus van der Kwast, Robert G. Bristow, Paul C. Boutros, and Housheng Hansen He

Nature Communications Paper

ONECUT2 is a driver of neuroendocrine prostate cancer

Authors

Haiyang Guo, Xinpei Ci, Musaddeque Ahmed, Junjie Tony Hua, Fraser Soares, Dong Lin, Loredana Puca, Aram Vosoughi, Hui Xue, Estelle Li, Peiran Su, Sujun Chen, Tran Nguyen, Yi Liang, Yuzhe Zhang, Xin Xu, Jing Xu, Anjali V. Sheahan, Wail Ba-Alawi, Si Zhang, Osman Mahamud, Ravi N. Vellanki, Martin Gleave, Robert G. Bristo, Benjamin Haibe-Kains, John T. Poirier, Charles M. Rudin, Ming-Sound Tsao, Bradly G. Wouters, Ladan Fazli, Felix Y. Feng, Leigh Ellis, Theo van der Kwast, Alejandro Berlin, Marianne Koritzinsky, Paul C. Boutros, Amina Zoubeidi, Himisha Beltran, Yuzhuo Wang & Housheng Hansen He

Funding

These studies were partially funded by a TFRI New Investigator Award in Understanding the function of circular RNA in tumour hypoxia to Dr. Housheng Hansen He.