Targeting this gene could kill prostate cancer

Researchers have recently discovered a new gene that plays an important role in promoting prostate cancer, and they have shown that turning it off can kill cancer cells.

They suggest that it could serve as a target for future treatments that may be used instead of — or in addition to — therapies that prostate cancer eventually becomes resistant to.

A paper now published in the journal Nature Genetics reports how blocking the gene — called AR-regulated long noncoding RNA 1 (ARLNC1) — killed cancer cells in prostate cancer cell lines.

Silencing ARLNC1 also shrank tumors in mouse models of prostate cancer, while increasing its expression made tumors grow larger.

Prostate cancer and therapy resistance

Prostate cancer develops when cells grow out of control in the prostate, which is a gland that adds fluid to semen as it passes through the urethra in a man's body. In the United States, prostate cancer is the second most common cancer in men.

Official estimates suggest that there will be 164,690 new cases of prostate cancer in the U.S. in 2018, accounting for 9.5 percent of all new cases of cancer.

Rates of death to prostate cancer have been falling steadily over the past 25 years, and now, more than 98 percent of men with the disease are likely to live more than 5 years following diagnosis.

Male hormones known as androgens are vital for the growth of prostate cells, including cancerous ones. The hormones interact with cells by binding to cell proteins called androgen receptors. This binding signals specific genes to promote cell growth.

Current treatments for prostate cancer target the androgen receptor in an attempt to block the signals that promote cell growth.

But while androgen therapy can be successful to start with, in most cases, the disease becomes resistant to treatment and develops into a form called "metastatic castration-resistant prostate cancer," which is much harder to treat.

Long noncoding RNAs

The new study builds on recent genetic research into "long noncoding RNAs (lncRNAs)," which are long RNA molecules of transcribed DNA that do not contain instructions for making proteins.

Because they were little understood, lncRNAs were thought to belong to the "dark matter" of the genome. However, interest has grown recently because they appear to be important for controlling cell biology.

New tools that analyze the "transcriptome" — that is, the "readout" of the genome in cells — have made it possible to study lncRNAs in specific types of cell, including prostate cancer cells.

In previous research, corresponding study author Arul M. Chinnaiyan, a professor of pathology and urology at the University of Michigan in Ann Arbor, and team had already picked out thousands of lncRNAs.

By analyzing the transcriptome of "prostate cancer cell lines and tissues," they found that one lncRNA in particular — called ARLNC1 — was "strongly associated" with androgen receptor signaling.

Positive feedback loop

They found that not only did the androgen receptor protein promote ARLNC1, but also that ARLNC1 stabilized levels of the androgen receptor protein — which, in turn, promoted more ARLNC1, thus creating a "positive feedback loop."

Tests in cells expressing the androgen receptor showed that silencing ARLNC1 led to death of cancer cells and halted tumor growth.

Further experiments with mouse models showed that increasing ARLNC1 made tumors grow larger, while silencing it shrank them.

The team concludes that "taken together," the findings support the idea that ARLNC1 maintains a "positive feedback loop" that strengthens androgen receptor signaling in the progression of prostate cancer.

Prof. Chinnaiyan and colleagues plan to continue investigating ARLNC1 in prostate cancer.

"This study identifies a feedback loop that we could potentially disrupt as an alternative to blocking the androgen receptor directly."

Prof. Arul M. Chinnaiyan