Silent DNA architecture helps block cancer cell growth

Researchers uncover new tumor suppression mechanism

Cancerous and precancerous cells can detect that they are abnormal and kill themselves, or remain alive indefinitely but cease proliferating, through two intrinsic processes called programmed cell death and cellular senescence. One goal of cancer chemotherapy is to help stimulate these potent antitumor processes.

Researchers at Cold Spring Harbor Laboratory on Long Island have recently shown that by locking cancer cells into a permanent state in which they remain alive but can no longer proliferate, cellular senescence contributes to successful outcomes following cancer therapy. Now, the same group has uncovered a precise molecular mechanism that helps trigger the “stop growing” response of cells. The study is published in the June 13 issue of the journal Cell.

“We think we have uncovered one reason why cancer cells can remain in limbo – alive but not proliferating – for very long periods of time. This long term suppression of cancer cell growth is an important antitumor response. Now that we have a handle on the precise mechanism of the response, we hope to ultimately find ways to harness it for treating cancer,” says Scott Lowe, who led the study.

Lowe and his colleagues found that cellular senescence involves the tight packaging of specific regions of chromosomal DNA into an inactive or silent architecture called heterochromatin.

To distinguish these newly identified regions of specialized DNA architecture from previously known forms of heterochromatin, the researchers dubbed such regions senescence-associated heterochromatic foci, or SAHF. Importantly, the study establishes that genes contained in these chromosomal regions are switched on in proliferating cells, but are switched off or “silenced” during cellular senescence.

Moreover, the researchers showed that the formation of SAHF is mediated by the action of a well-known tumor suppressor protein called Rb. Interestingly, the study reveals that the formation of SAHF maps to genes known from previous studies to be switched off through the action of Rb.

The study provides the first detailed view of how the tumor suppressor Rb establishes regions of specialized DNA architecture in the cell. Because such architecture is extremely stable, the research may explain the irreversibility of the senescent state, namely, why cells rarely if ever start growing again once they senesce.

The scientists studied a form of cultured human cells called IMR90 cells, which are commonly used to study cellular senescence.

Lowe is a Professor of Cancer Research at Cold Spring Harbor Laboratory and Deputy Director of the Laboratory’s NCI-designated Basic Cancer Center. He was joined in the study by eight other scientists, including postdoctoral fellow and lead author of the study, Masashi Narita, and by CSHL Professors David Spector and Gregory Hannon.