Groundbreaking discovery has potential to improve therapies for cancer and other diseases

December 15, 2016

LONDON, ON - The Retinoblastoma protein (pRB) has long been studied for its role in cell growth and the prevention of cancer. In a new study by Lawson Health Research Institute, scientists have discovered that pRB plays another, larger role with the potential to enhance therapies for cancer and other diseases such as HIV.

Most of the DNA in the human genome is composed of repetitive sequences called 'junk DNA'. Many of these are leftover pieces of ancient infections. These sequences are thought to have no positive contribution to the human body and are normally kept silent. If they do replicate, they can be reinserted into the human genome where they damage genes and contribute to diseases such as cancer.

Led by Dr. Fred Dick, the team of Lawson researchers is the first to discover that pRB works with another protein called EZH2 to silence repetitive sequences of DNA. EZH2 adds a tag to repetitive sequences, marking regions to be shut off or unexpressed by a cell. It appears that the retinoblastoma protein (pRB) acts as a vehicle that delivers EZH2 to those repetitive sequences.

"This is a novel discovery that changes the way cancer geneticists have thought about pRB and EZH2. Most researchers never dreamt that these two proteins have thousands of locations in our DNA that they are regulating," said Dr. Dick, a scientist at Lawson and the London Regional Cancer Program at London Health Sciences Centre (LHSC). "This opens up endless avenues for therapeutics across a multitude of diseases, including anti-viral agents. It could give patients new choices in the treatment of their disease."

A number of drugs are being tested to either activate pRB function or to block EZH2, focusing on the role these two proteins play in cell growth. pRB is understood to control cell growth while EZH2 can become overactive in some cancers and silence other genes that control cell growth.

This new study predicts that drugs called EZH2 inhibitors may also be used to help the immune system target cancers. Blocking EZH2 will lead to expression of 'junk DNA', so cancer cells will appear to the immune system as if they are infected by a virus. The immune system can then target and kill these cells.

"This discovery has significant implications for the use of immunotherapies and the importance of pRB testing in cancer diagnosis and prognosis," said Dr. Dick, also a professor in the Departments of Biochemistry and Oncology at the Schulich School of Medicine & Dentistry, Western University. "It suggests that cancers that are pRB deficient will respond better to immunotherapies since repeats will be expressed, and those that are pRB positive might respond well to a combination of EZH2 inhibitors and immunotherapies."

The research also has implications for a number of other diseases. HIV is thought to hide in immune memory cells in a similar way to 'junk DNA'. Since these cells cannot be targeted by conventional treatments, patients remain HIV positive. EZH2 inhibitors could be used to reveal the virus' hiding place by forcing the virus to express. Active viral gene expression could then be targeted using drugs that are already on the market.

"This study enhances our understanding of pRB's functions and its role as a tumor suppressor," said Dr. Dick. When the pRB-EZH2 complex was eradicated in a mouse model, there was no regulation of 'junk DNA' and the mice eventually developed cancer. Completely eliminating the silent repetitive sequences for long periods of time can lead to instability of the genome and formation of disease. "We have been researching pRB for years and have never seen such a significant effect. It's clear that the pRB-EZH2 complex is extremely important to both the genesis and the treatment of cancer."

The study, "An RB-EZH2 Complex Mediates Silencing of Repetitive DNA Sequences", is published in the international journal, Molecular Cell. Its significance was also highlighted by Cancer Discovery. This is another example of how Lawson Health Research Institute is working to make Ontario healthier, wealthier and smarter.
Lawson Health Research Institute. As the research institute of London Health Sciences Centre and St. Joseph's Health Care London, and working in partnership with Western University, Lawson Health Research Institute is committed to furthering scientific knowledge to advance health care around the world.

For more information, please contact:

Robert DeLaet
Communications & External Relations vLawson Health Research Institute
(t) 519-685-8500 ext. 75664
(c) 519-619-3872

Connect with Lawson Health Research Institute
Twitter: @lawsonresearch
Facebook: /lawsonhealthresearchinstitute

Lawson Health Research Institute

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to