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<p>In order to propagate a solid tumor, cancer cells must adapt to and survive under
various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis.
Additionally, cancer cells exposed to these stresses are more resistant to therapies,
more likely to metastasize and often are worse for patient prognosis. While the presence
of these stresses is generally negative for cancer patients, since these stresses
are mostly unique to the TME, they also offer an opportunity to develop more selective
therapeutics. If we achieve a better understanding of the adaptive mechanisms cancer
cells employ to survive the TME stresses, then hopefully we, as a scientific community,
can devise more effective cancer therapeutics specifically targeting cancer cells
under stress. To systematically identify genes that modulate cancer cell survival
under stresses, we performed shRNA screens under hypoxia or lactic acidosis. From
these screens, we discovered that genetic depletion of acetyl-CoA carboxylase alpha
(ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced
apoptosis. Furthermore, the loss of ACLY or ACC1 reduced the levels and activities
of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from
hypoxia-induced apoptosis and led to remarkably similar transcriptional responses
as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis
found that while α-ketoglutarate levels decrease under hypoxia in control cells, α-ketoglutarate
was paradoxically increased under hypoxia when ACC1 or ACLY were depleted. Supplementation
with α-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased
expression and activity of ETV4, likely via an epigenetic mechanism. Therefore, ACC1
and ACLY regulated the levels of ETV4 under hypoxia via increased α-ketoglutarate.
These results reveal that the ACC1/ACLY-α-ketoglutarate-ETV4 axis is a novel means
by which metabolic states regulate transcriptional output for life vs. death decisions
under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics,
our findings suggest that the use of these inhibitors will need to be carefully considered
with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly,
our screen provides a framework for studying additional tumor cell stress-adaption
mechanisms in the future.</p>
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