Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer.
Catríona M DowlingKate E R HollinsheadAlessandra Di GrandeJustin PritchardHua ZhangEugene T DillonKathryn E HaleyEleni PapadopoulosAnita K MehtaRachel BleachAndreas U LindnerBrian MooneyHeiko DüssmannDarran O'ConnorJochen H M PrehnKieran WynneMichael T HemannJames E BradnerAlec C KimmelmanJennifer L GuerrieroGerard CagneyKwok-Kin WongAnthony G LetaiTríona Ní ChonghailePublished in: Science advances (2021)
Triple-negative breast cancer (TNBC) is a subtype of breast cancer without a targeted form of therapy. Unfortunately, up to 70% of patients with TNBC develop resistance to treatment. A known contributor to chemoresistance is dysfunctional mitochondrial apoptosis signaling. We set up a phenotypic small-molecule screen to reveal vulnerabilities in TNBC cells that were independent of mitochondrial apoptosis. Using a functional genetic approach, we identified that a "hit" compound, BAS-2, had a potentially similar mechanism of action to histone deacetylase inhibitors (HDAC). An in vitro HDAC inhibitor assay confirmed that the compound selectively inhibited HDAC6. Using state-of-the-art acetylome mass spectrometry, we identified glycolytic substrates of HDAC6 in TNBC cells. We confirmed that inhibition or knockout of HDAC6 reduced glycolytic metabolism both in vitro and in vivo. Through a series of unbiased screening approaches, we have identified a previously unidentified role for HDAC6 in regulating glycolytic metabolism.
Keyphrases
- histone deacetylase
- cell cycle arrest
- oxidative stress
- induced apoptosis
- small molecule
- endoplasmic reticulum stress
- mass spectrometry
- cell death
- genome wide
- high throughput
- pi k akt
- single cell
- high resolution
- transcription factor
- dna methylation
- stem cells
- young adults
- cell therapy
- high performance liquid chromatography
- combination therapy