03.2020 | THE SCIENTIST 29to create an MS-like condition. No matter their gonads, XX mice
were more susceptible to developing the condition.^18 In a 2019 paper,
Voskuhl reported that T cells from XX mice expressed more of a
particular escapee, the gene for the transcription factor KDM6A.
Knocking out the Kdm6a gene diminished neuroinflammation and
protected mice from developing MS-like symptoms.^19 “This is a really
nice gene to target for therapy,” says Voskuhl. “It’s a master switch for
so many genes involved in autoimmunity.”
In fact, the diabetes drug metformin is known to regulate KDM6A,
blocking its demethylase activity to increase gene silencing across the
genome. In an MS mouse model, metformin treatment minimized
symptoms.^20 Voskuhl plans to test the medicine further in mice and
in people with MS, and says she thinks it might treat other autoim-
mune conditions, too.
KDM6A escape isn’t all bad news for women’s health. The gene is
also a tumor suppressor.
Men are about 20 percent more likely to get cancer than women,
and in some cancers, the rate in men is more than double that
in women. Scientists had long assumed that was because men
were more likely to smoke, drink, or toil in factories suffused with
toxic chemicals. But recent epidemiology suggests those aren’t the
only factors.
Several years ago, Andrew Lane, a physician-scientist at the
Dana-Farber Cancer Institute in Boston, noticed—as others had—
that certain tumor suppressors located on the X chromosome were
more often mutated in male cancer patients than in female patients.
In the case of KDM6A, for example, mutations are more common in
men’s cancers than in women’s.
At first, Lane couldn’t fathom how this could be so. With one X
inactivated, shouldn’t one KDM6A mutation be sufficient to inactivate
the tumor suppressor? The “Aha” moment came a year or two later,
when he discovered Brown’s and Disteche’s work describing X escape
on PubMed. Lane hadn’t heard of X escape before, but suddenly he
wondered—might escapees be protecting women?
Inspired, he developed what he calls the Escape from X-Inacti-
vation Tumor Suppressor, or EXITS, hypothesis: by expressing spare
tumor suppressors from the inactive X, women may stave off can-
cer. To test the idea, Lane teamed up with cancer genomics experts
at the Broad Institute of MIT and Harvard to analyze cancer muta-
tions from 4,126 patients, with 21 different tumor types, from Broad
data and the National Cancer Institute’s Cancer Genome Atlas. The
researchers scanned all 23 chromosome pairs for genes that skewed
toward more mutations in men than in women and got six hits,
including KDM6A.^21 Four were known tumor suppressor genes, and
all were on the X chromosome.
Of the six X-linked genes identified in Lane’s study, five had been
seen escaping before. The sixth, a gene for a chromatin remodeler
and tumor suppressor called ATRX, was a surprise. It had neverbeen listed as an escapee. But Lane found hints, in GTEx data, that
ATRX can escape in brain tissue. The results support the idea that
having a second, expressed copy of these tumor suppressor genes
can save women from developing cancer, whereas men, with only
one X, can succumb to disease after a single mutation in those genes.
Researchers predict that there are more escapees left to find, across
different types of cells, tissues, individuals, and probably people of
different ages. “We’re just taking the first step in really understand-
ing the full complexity of this phenomenon,” Tukiainen says. “There
is definitely a lot more to explore so we can complete the picture.” gAmber Dance is a freelance science journalist living in the Los
Angeles area. Read her work or reach out at AmberLDance.com.References- M.F. Lyon, “Gene action in the X-chromosome of the Mouse (Mus musculus L .) ,”
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THE SCIENTIST to cancer sex bias,” Nat Genet, 49:10–16, 2017.
STAFF
We’re just taking the fi rst step in really
understanding the full complexity of this
phenomenon.
—Taru Tukiainen, Institute for Molecular Medicine Finland