Acute myeloid leukemia (AML) is a hematological malignancy with rapid disease progression and often becomes lethal without treatment. Development of effective new therapies is essential to improve the clinical outcome of AML patients. Enhancer of zeste homolog 2 (EZH2) and lysine specific demethylase 1 (LSD1) play important roles in epigenetic regulation and their altered expressions have been observed in cancer. Although EZH2 and LSD1 have opposite histone methylation functions, we found that both enzymes were paradoxically up-regulated in AML cells. Importantly, a combined inhibition of EZH2 and LSD1 resulted in a synergistic activity against AML in vitro and in vivo. Such synergy was mechanistically correlated with up-regulation of H3K4me1/2 and H3K9Ac and down-regulation of H3K27me3, leading to a decrease of anti-apoptotic protein Bcl-2. These epigenetic alterations also compromised the mitochondrial respiration capacity and glycolytic activity and resulted in ATP depletion, a key event contributing to the potent cytotoxic effect of the drug combination. Taken together, our work identified a novel therapeutic approach against AML by combining two small molecules that inhibit different histone methylation-modulating proteins with apparently opposite enzyme activities. Such a new drug combination strategy likely has significant clinical implications since epigenetic modulators are currently in clinical trials.
Cancer Letters – Elsevier
Published: Jan 28, 2018
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.
Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera