ETHE1 overexpression promotes SIRT1 and PGC1alpha mediated aerobic glycolysis, oxidative phosphorylation, mitochondrial biogenesis and colorectal cancer.
ETHE1 overexpression promotes SIRT1 and PGC1alpha mediated aerobic glycolysis, oxidative phosphorylation, mitochondrial biogenesis and colorectal cancer.
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DOI：
10.18632/oncotarget.26958
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发表时间：
2019-06-18
期刊：
影响因子：
--
通讯作者：
Lipkin, Steven
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文献类型：
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作者：
Witherspoon, Mavee;Sandu, Davinder;Lipkin, Steven
乙基丙二酸脑病蛋白1 （ETHE1）是一种调节细胞H2S水平的硫双加氧酶。我们之前证明了家族性腺瘤性息肉病（FAP）患者的“单击”结肠上皮细胞中ETHE1的表达显著增加。在这里，我们报告了表型正常的FAP结肠粘膜中ETHE1表达水平升高和线粒体密度增加。我们还发现，在结直肠癌（CRC）细胞系中，ETHE1的组成性表达增加了有氧糖酵解（“Warburg效应”）、氧化磷酸化和线粒体生物发生，从而消耗H2S，从而减轻了对磷酸二酯酶（PDE）的抑制，并增加了单磷酸腺苷（AMP）水平。这导致了能量感应amp激活蛋白激酶（AMPKp）、Sirtuin1 （SIRT1）和过氧化物酶体增殖体激活受体γ辅助激活因子1α (pgc1 α)的激活，后者是线粒体生物发生的主要调节因子。相比之下，shRNA沉默ETHE1可降低PDE活性、AMPKp/SIRT1/ pgc1 α水平和线粒体生物发生。ETHE1的组成性表达加速了CRC细胞异种移植和原位患者来源的异种移植CRC细胞在体内的生长。总的来说，我们的数据表明ETHE1表达水平升高是一种新的生物标志物和预防结直肠癌肿瘤发生的潜在治疗靶点。
Ethylmalonic Encephalopathy Protein 1 (ETHE1) is a sulfur dioxygenase that regulates cellular H2S levels. We previously demonstrated a significant increase of ETHE1 expression in "single-hit" colon epithelial cells from crypts of patients with Familial Adenomatous Polyposis (FAP). Here, we report elevated levels of ETHE1 expression and increased mitochondrial density occurring in-situ in phenotypically normal FAP colorectal mucosa. We also found that constitutive expression of ETHE1 increased aerobic glycolysis ("Warburg effect"), oxidative phosphorylation, and mitochondrial biogenesis in colorectal cancer (CRC) cell lines, thereby depleting H2S which relieved the inhibition of phosphodiesterase (PDE), and increased adenosine monophosphate (AMP) levels. This led to activation of the energy sensing AMP-activated protein kinase (AMPKp), Sirtuin1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC1alpha), a master regulator of mitochondrial biogenesis. By contrast, shRNA silencing of ETHE1 reduced PDE activity, AMPKp/SIRT1/PGC1alpha levels and mitochondrial biogenesis. Constitutive expression of ETHE1 accelerated both CRC cell xenograft and orthotopic patient derived xenograft CRC cell growth in vivo. Overall, our data nominate elevated ETHE1 expression levels as a novel biomarker and potential therapeutic target for the prevention of CRC tumorigenesis.