On-Off Switch Controls Cancer

Scientists have long known that cancer results from uncontrolled cell proliferation. Over the past several decades, investigations across the globe have looked into the molecular origins of unchecked cell growth. However, despite progress in understanding how cells lose their ability to regulate themselves, no effective universal treatment for cancer has emerged.

A significant stride has been made with the recent discovery that tumorigenesis may be controlled by an endogenous molecular “on-off ” switch. This switch presents a novel and potentially universal target for treatment.

The role that RNA may play in controlling this switch was published in the Proceedings of the National Academy of Sciences by Alan Garen, Professor of Molecular Biophysics and Biochemistry, and his former postdoctoral fellow, Xu Song. In addition to expanding our body of knowledge of cell growth and division, the paper also posed a fresh approach to studying the molecular mechanisms of tumorigenesis.

RNA is most commonly identified as an intermediate molecule in the process of synthesizing protein from DNA. However, research during the twentieth century implicated this molecule in a multitude of other roles, such as catalyzing chemical reactions, linking amino acids to form proteins, and regulating the expression of gene products. These collective results suggested that RNA is a diverse molecule that can function in many ways.

Adding to RNA’s burgeoning repertoire, Garen made the surprising discovery that the macromolecule can drive cell proliferation. “Like most scientific discoveries, it involved serendipity,” said Garen.

All multicellular organisms arise from a single cell, which then divides numerous times in early development. The division stops at a certain stage, where each cell is assigned a function in a process termed differentiation and directed to a fixed position where it will then work with neighboring cells to perform a specific function.

However, this does not mean that cell division completely ceases as a multicellular organism matures. Cell division may be revived to repair loss or damage caused by either external or internal sources. In humans, for instance, some cells such as skin cells constantly undergo division to counteract the loss of other cells due to daily activities. Still, there are particular subsets of cells, such as brain cells, that seldom divide after initial early development.

During cell growth and division, special proteins such as repressor proteins regulate the cell cycle by controlling the transcription of genes. For example, one tumor suppressing protein called PSF represses the transcription of proto-oncogenes, which code for factors that enhance cell growth and division during early development. If this repression is not effectively controlled during later stages of an organism’s lifecycle, the proto-oncogene can readily become an oncogene, which is cancer causing.

It is currently known that a repressor protein contains a DNA binding domain that interacts with the genetic material to halt transcription. Interestingly, the protein also has an RNA binding domain. Motivated by this finding, Garen sought to understand the molecular reasoning for the additional binding domain. Specifically, he wondered if the RNA binding domain was involved in repression.

In early development, the repressor protein cannot function because many RNA molecules are bound to it. After cell differentiation is complete, RNAs disappear so that the repressor can act on the gene in order to prevent further cell divisions. In tumor cells, however, a large amount of RNA reappears, inhibiting the repressor’s function and ultimately causing the cells to divide in an uncontrollable fashion. These findings suggest a RNA-based “on-off ” switch for cancer.

Garen and colleagues further explored this discovery by experimenting on mice and human cells. When they transfected the RNA that binds to the tumor suppressor protein PSF, the protein was inhibited, cell division occurred, and tumor developed. However, when the researchers increased the concentration of the repressor proteins relative to the amount of transfected RNA, mice did not develop tumors.

In addition, when the researchers selectively destroyed the RNA transfected earlier with micro- RNA (miRNA), no tumor cells were detected.

In terms of using this “on-off ” switch as a therapeutic target, Garen noted, “If you are able to either introduce the gene to make a lot of repressor protein or introduce the little RNA that destroys the big RNA… one could potentially treat many or even all types of cancers.”