Master regulator of key cancer gene found, offers new drug target

June 25, 2014, University of Minnesota

A key cancer-causing gene, responsible for up to 20 percent of cancers, may have a weak spot in its armor, according to new research from the Masonic Cancer Center, University of Minnesota.

The partnership of MYC, a gene long linked to cancer, and a non-coding RNA, PVT1, could be the key to understanding how MYC fuels cancer cells. The research is published in the latest issue of the journal Nature.

"We knew MYC amplifications cause cancer. But we also know that MYC does not amplify alone. It often pairs with adjacent chromosomal regions. We wanted to know if the neighboring genes played a role," said lead author Anindya Bagchi, Ph.D., assistant professor in the University of Minnesota Medical School, the College of Biological Sciences and member of the Masonic Cancer Center. "We took a chance and were surprised to find this unexpected and counter-intuitive partnership between MYC and its neighbor, PVT1. Not only do these genes amplify together, PVT1 helps boost the MYC protein's ability to carry out its dangerous activities in the cell."

Contributors to this research include Yuen-Yi Tseng, graduate student with Anindya Bagchi, David Largaespada, Ph.D., professor in the College of Biological Sciences, Yasuhiko Kawakami, Ph.D., assistant professor in the College of Biological Sciences, York Marahrens, Ph.D., associate professor in the College of Biological Sciences and Kathryn Schwertfeger, Ph.D., assistant professor in the University of Minnesota's Medical School.

Bagchi and his team focused on a region of the genome, 8q24, which contains the MYC gene and is commonly expressed in cancer. The team separated MYC from the neighboring region containing the non-coding RNA PVT1. Using a specialized gene manipulation technique called chromosome engineering, researchers developed genetically engineered mouse strains in three separate iterations: MYC only, the rest of the region containing PVT1 but without MYC and the pairing of MYC with the regional genes.

The expected outcome, if MYC was the sole driver of the cancer, was tumor growth on the MYC line as well as the paired line. However, researchers found growth only on the paired line. This indicates MYC is not acting alone and needs help from adjacent genes.

"The discovery of this partnership gives us a stronger understanding of how MYC amplification is fueled. When cancer promotes a cell to make more MYC, it also increases the PVT1 in the cell, which in turn boosts the amount of MYC. It's a cycle, and now we've identified it, we can look for ways to uncouple this dangerous partnership," said Largaespada.

Testing this theory of uncoupling, researchers looked closely at several breast and colorectal cancers which are driven by MYC. For example, in colorectal cancer lab models, where a mutation in the beta-catenin gene drives MYC to cancerous levels, eliminating PVT1 from these cells made the tumors nearly disappear.

"Finding the cooperation between MYC and PVT1 could be a game changer. We used to think MYC amplification is the major issue, but ignored that other co-amplified genes, such as PVT1, can be significant," said Tseng, the paper's first author. "In this study, we show that PVT1 can be a key regulator of MYC protein, which can shift the paradigm in our understanding of MYC amplified cancers."

MYC has been notoriously elusive as a drug target. By uncoupling MYC and PVT1, researchers suspect they could disable the cancer growth and limit MYC to pre-cancerous levels. This would make PVT1 an ideal drug target to potentially control a major cancer gene.

"This is a thrilling discovery, but there are more questions that follow," said Bagchi. "Two major areas present themselves now for research: will breaking the nexus between MYC and PVT1 perform the same in any MYC-driven , even those not driven by this specific genetic location? And how is PVT1 stabilizing or boosting MYC within the cells? This relationship will be a key to developing any drugs to target this mechanism."

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