New insights into androgen’s action could boost battle against prostate cancer
Researchers at UVA Cancer Center have
unveiled important new insights into how hormones known as androgens act on our
cells — and the discovery could boost efforts to develop better treatments for
prostate, ovarian and breast cancers.
The findings shed light on how
androgens interact with their receptors inside cells to affect gene activity.
This process is important in both healthy cells and certain cancers. Hormone
therapy for prostate cancer, for example, aims to reduce the amount of androgen
in the body, or to stop it from fueling the cancer cells. However, the approach
does not work for some men, and for others it eventually fails. So scientists
are eager to better understand how our cells — and cancer — interact with
“Our study reveals a new
mechanism for how androgen regulates communication within prostate cancer
cells,” said Bryce M. Paschal, PhD, of the University of Virginia School
of Medicine’s Department of Biochemistry and Molecular Genetics.
“Anti-androgen therapies continue to be the cornerstone for prostate cancer
therapy. The better we understand how androgens work, the better clinicians
will be positioned to understand why it fails, and how even better therapies
can be designed.”
Androgen and Cancer
In a new paper in the scientific
journal Nature Communications, Paschal and his colleagues describe
how a complex signaling system regulates androgen receptor activity. The
system, they found, uses a “writer” and a “reader” to
modify cellular proteins — sort of like how a computer reads and writes
Scientists have appreciated the
importance of these modified proteins, but understanding just how they
influence the androgen receptors has been difficult. One key to the regulation
process, found by Paschal and his SOM team, is an enzyme, Parp7, produced by the
PARP7 gene. Parp7 is part of a family of enzymes involved in important cellular
functions including DNA repair.
Certain cancer drugs already target
certain Parp enzymes; these drugs are used to treat prostate, ovarian and
breast cancers in patients who have mutations in DNA-repair genes. And while
androgens are usually discussed in the context of prostate cancer, androgens
may be important in ovarian and breast cancer as well.
Paschal’s new findings offer fresh
insights into these Parp drugs and could lead to improved treatments that help
patients get the best outcomes. Further, Paschal and his team found lower
levels of Parp7 in prostate cancer that has spread to other parts of the body
than in the initial tumors. That may suggest that a reduction in Parp7 is
associated with the progression of the disease, the researchers say.
With their new androgen insights,
Paschal and his colleagues have provided scientists with important new
directions to explore in the battle against prostate and other cancers.
“Our next steps will be to use
preclinical models to determine the role this pathway plays in prostate cancer
progression, and whether inhibition of the pathways slows disease,” Paschal
said. “We are very excited by what we have learned thus far. Our study
emphasizes there is still so much to be learned, and that basic science plays a
critical role in defining the molecular context for enzyme and drug action.
- Chun-Song Yang, Kasey Jividen, Teddy Kamata,
Natalia Dworak, Luke Oostdyk, Bartlomiej Remlein, Yasin Pourfarjam, In-Kwon
Kim, Kang-Ping Du, Tarek Abbas, Nicholas E. Sherman, David Wotton, Bryce M.
Paschal. Androgen signaling uses a writer and a reader of ADP-ribosylation
to regulate protein complex assembly. Nature Communications,
2021; 12 (1) DOI: 10.1038/s41467-021-23055-6