The Scientist - 03.2020

03.2020 | THE SCIENTIST 29

to 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 never

been 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.” g

Amber Dance is a freelance science journalist living in the Los

Angeles area. Read her work or reach out at AmberLDance.com.

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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