Cell Systems: X chromosome silencing for some male cancers

Humans only need one active X chromosome, which means that a person with two X chromosomes must turn off one of them to avoid doubling
the protein product.
The gene that inactivates one X chromosome, called XIST, encodes a long piece of noncoding RNA that wraps and epigenetically suppresses the extra X chromosome early in development in people with two X chromosomes
.
Previously, XIST was associated
with female cancers as well as testicular cancer.
Now, in a study published Nov.
9 in Cell Systems, researchers have also found XIST activity
in cancers of various body tissues in men.

Irregular XIST activity has been linked to testicular cancer, which is caused
by male germ cells.
But in the new study, the researchers found high levels of XIST RNA
in male somatic cells sampled from cancer tissue.
While the study did not show a causal relationship between XIST expression and male cancer, it found that XIST turned off the expression of X chromosome genes in adult male somatic cells that are thought to require proteins encoded on the X chromosome
.
The researchers say this silence could have harmful effects
.

"We already know that testicular cancer has XIST, and we may suspect that XIST is also present in some other cancers, but actually doing such detailed studies on all types of cancer – it's really fascinating and shows that we're missing something
.
"

Study co-author Srinivas Wiswanathan, an oncologist at the Dana-Farber Cancer Institute in Boston, explained that the finding was "somewhat accidental.
"

He and his team have been analyzing cellular transcriptome information
for XIST RNAs present in the Cancer Genome Atlas Project (TCGA) database.
They expected to see XIST in tumors, but only in female cell and testicular
cancers.
Wiswanathan said the researchers "happened to notice that the sample annotated as male also expressed [XIST]
.
" "On further study, they found that 4% of all male cancers expressed XIST, and 74% of these cancers were testicular cancers
.
But the other 26 percent came from other tissues, including the lungs, kidneys, heart and liver
.
"The traditional idea is that XIST is a transcription exclusive to women," Wiswanathan said
.
"(Men) should not have X chromosome inactivation
.
[This] is very surprising
.
”

To ensure that the expression of XIST did not come from healthy cells, the team used RNAseq data to measure the amount of
XIST RNA normally present in healthy tissues in both men and women.
When they compared the pooled data, they found that cancer cells expressed higher levels of XIST on average than healthy male tissue—a level comparable to
female tissue.
If the XIST expression level of the cell is similar to that of female tissue, it is labeled XIST+
.
In a few cases, researchers took samples
from healthy and cancerous tissue from the same person.
In these cases, they found expression of XIST only in cancer cells
.

Using TCGA's genome sequencing data, the researchers found that XIST expression was associated with X-chromosome aneuploidy, a phenomenon
in which cells contain multiple copies of a chromosome, in many samples.
DNA in cancer cells is notoriously unstable, and these cells have high aneuploidy because the cells divide incompletely
.
However, only about half of XIST+ cancers have multiple X chromosomes
.
Researchers are still looking for a mechanism to explain XIST's link
to cancer.

According to RNAseq and ATACseq (Transposase Reachable Chromatin Sequencing Technology, a technique to assess how well DNA is reachable to transcriptional proteins), XIST RNA also plays its usual role
in silencing gene expression on the X chromosome when it appears in cancer cells.
The researchers found that fewer X chromosome genes were expressed in cancer cells containing XIST, suggesting that XIST may silence X-related genes
.
In another experiment, they used a cancer cell line known to express XIST, knocked out transcripts, and found that they could reverse the silencing effect and restore gene expression
.
This suggests that XIST is indeed responsible
for the silent effect.

Brown said the study "provides evidence for a very interesting concept: XIST, obtained through the body, may still have the effect
of silencing chromosomes.
" This raises the question, she said, "Which genes in somatic cells are sensitive to the presence of XIST?"

While these findings do not have any immediate clinical implications, the study highlights the need
for researchers to take sex into account when searching for new therapeutic targets.
He added that researchers often ignore sex when analyzing gene expression in cancer cells, which may be why researchers have previously missed the connection
with XIST.

"Sex itself is a biomarker
.
I don't think this has been given the attention
it deserves.
"This is an example
of a biological baseline difference between men and women leading to cancer-specific differences.
"