RNA strand may inhibit tumor-suppressing proteins

A pioneering Yale biochemist who helped discover the stop codon — DNA’s signal for terminating a protein sequence — in the 1960s may have just brought Yale’s researchers one step closer to curing cancer. Staff reporter Lindsay Gellman investigates.

Last week, Alan Garen, professor of molecular biophysics and biochemistry, made public his novel findings that a particular strand of RNA prevents tumor suppressor proteins — which bind to DNA and inhibit its replication — from performing their function. The proteins’ detachment from DNA, in turn, allows for unregulated cell division that could lead to malignant tumors.

Garen’s discovery, published in the Sept. 7–11 edition of Proceedings of the National Academy of Sciences, confirms yet another novel function of RNA, previously thought to act only as an intermediary between DNA and proteins, said Daniel DiMaio, vice chairman of genetics at the Yale School of Medicine and scientific director of the Yale Cancer Center.

“By focusing on cell proliferation as the key to the initiation of tumor formation,” Garen said, “we determined that RNAs play a central role in that process.”

AN EVOLUTIONARY ARTIFACT

Why, then, do our cells contain this seemingly harmful strand of RNA?

Before he conducted his research, Garen said the function of the RNA-binding site on these tumor suppressor proteins was not understood.

Now Garen’s team has illuminated that the RNA strand, called VL30-1, and its corresponding binding site on tumor-suppressor proteins are necessary for early growth and development. Garen explained that VL30-1 RNA, a noncoding string of nucleotides, inhibits proteins that prevent cells from dividing rapidly, allowing them to divide quickly so that, for example, a zygote can develop into a fetus.

Problems occur, he said, when the RNA continues to bind to tumor suppressor proteins in healthy adult cells. This finding provides researchers with the advantage of targeting this biomolecular pathway when developing cancer treatments.

Garen’s work marks a significant advancement in the field of cancer research, DiMaio said.

“The regulatory circuit he describes may provide a new target for innovative approaches to prevent and treat cancer,” he said.

Xu Song, a researcher at Sichuan University in Chengdu, China, and one of the study’s co-authors, agreed the new finding has potential clinical applications in cancer treatment. VL30-1 shows levels of elevated expression in tumor cells, and decreasing its levels may suppress tumors, he said. Alternatively, Garen said, tumor-suppressor proteins could be added to the cell, overwhelming VL30-1 and preventing cell division.

‘A MAGIC BULLET’?

As researchers at Yale and elsewhere continue to develop increasingly effective treatments for cancer as well as a more profound understanding of the disease, the concept of a cure remains a topic of debate.

What would such a cure entail? Is a cure even a possible outcome of future research, or are improved treatment therapies the best we can hope for?

“Everybody would like a magic bullet,” Garen said. “The problem is, there are many types of cancer.”

Garen’s frequent collaborator William Konigsberg, professor of molecular biophysics and biochemistry, agreed that the diversity within the disease itself poses a challenge to researchers seeking a cure.

“Cancer really represents many different diseases with different origins,” Konigsberg said, citing liver cancer and prostate cancer as examples. “I don’t think there’s … an all-encompassing therapeutic. You won’t find that.”

While this work may eventually lead to new developments in cancer treatment, his findings mainly represent theoretical developments in molecular biochemistry, Garen said.

Garen said he believes his team previously identified a more direct and effective method of treating cancer.

“About six years ago, we developed a way to specifically destroy the blood vessels necessary for the tumor’s survival without hurting healthy cells,” Garen said. Though the method worked well in mice, the project’s clinical development has been stalled due to administrative problems, he added.

This procedure for cancer therapy is effective, Garen explained, but does not increase researchers’ understanding of the mechanism behind the development of tumors.

He analogized the blood vessel therapy to the primitive use of newly discovered antibiotics in the late 1920s: “When penicillin was discovered nobody knew how it worked, only that it did work.”

PEELING THE ONION

Though the RNA study is not as immediately applicable to cancer treatment as the blood vessel technique, Garen said it interests him on a deeper level because it adds to a fundamental comprehension of the molecular events that can lead to cancer.

The path to a cure, he said, must ultimately be one based on an “understanding of the basic mechanisms” of tumor cells.

Still, Konigsberg noted that he was optimistic about current research into micro RNA molecules, as well as combining different therapeutic avenues, such as chemotherapy, with genetics-based therapy.

For Garen and his team, the new findings raise as many questions as they provide answers.

Now that he has identified the specific RNA molecule that is binding improperly, the next step is to understand why the RNA protein binding system sometimes malfunctions to potentially cause cancer, Garen said.

“It’s an onion,” Garen said of cancer research. “As you peel back the skin, you reveal new layers.”

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