New research led by McGill’s Goodman Cancer Research Centre improves our understanding of micro㽶Ƶs
A new collaborative study, led by researchers at 㽶Ƶ’s Goodman Cancer Research Centre (GCRC), and published in the journal Molecular Cell, set out to solve this mystery, uncovering novel functions for polycistronic micro㽶Ƶs and showing how cancers such as lymphoma twist these functions to reorganize the information networks that control gene expression.
A discovery thanks to a single oncogene
The researchers made their discovery by examining how strongly the oncogenic micro㽶Ƶ polycistron miR-17-92 was over-expressed in several types of cancer. Surprisingly, this led to only small increases in the mature micro㽶Ƶ expression in the same types of cells. This meant a lot was happening during their biogenesis, especially in cancer, and that there may be more to the purpose of micro㽶Ƶ polycistrons than previously thought.
“Why some micro㽶Ƶs are expressed as polycistrons, and how cancers such as lymphoma change micro㽶Ƶ biogenesis were not known,” explains Dr. Thomas Duchaine, Professor in the Department of Biochemistry at McGill, member of the GCRC and the study’s senior author. “We were able to identify some mysterious steps in micro㽶Ƶ biogenesis that occur in cell nuclei, which had been completely missed for the nearly 20 years since the discovery of the conservation of micro㽶Ƶs.”
Understanding micro㽶Ƶs’ role in cancer
While researchers knew that micro㽶Ƶs are important in a broad variety of cancers, how and why was not fully understood. “We discovered an entirely new function for micro㽶Ƶ polycistrons and showed how deep an impact it has in certain types of cancer,” notes Dr. Duchaine. The findings will help make sense of many of the genomic reorganizations that occur in micro㽶Ƶ loci in those cancers. “We also think this may be happening in physiological conditions, early in development, in embryonic stem cells for example, in placenta, and in other types of tumours.”
Knowing what drives specific types of cancer is critical in stratifying cancer sub-types, in developing new therapeutic strategies, or anticipating treatment outcomes in precision medicine.
“The breadth of the impact of the amplification of a single micro㽶Ƶ locus on the gene networks is pretty amazing, in my opinion,” says Dr. Duchaine. “Especially considering that this occurs through a mechanism entirely outside of the traditional targeting function of micro㽶Ƶs. We are not done understanding micro㽶Ƶ mechanistics. I am always amazed at how complex their functional relationships are within our genomes.”
While it is not always easy to anticipate the practical implications of basic research findings, Dr. Duchaine believes that they will be diverse. “Besides forcing a reinterpretation of the function of the miR-17-92 proto-oncogene, it will prompt new potential therapeutic strategies. For example, the depth of the impact on the gene network in cells wherein miR-17-92 is amplified indicates a completely different gene network state. To me, this is a screaming opportunity for the testing of genotype-specific treatments in a precision medicine perspective.”
“Oncogenic biogenesis of pri-miR-17~92 reveals hierarchy and competition amongst polycistronic micro㽶Ƶs,” by A. Donayo, T. Duchaine, et al, was published online June 26 in Molecular Cell.