Abstract
Genomic alterations of tumor suppressorsoften encompass collateral protein-coding genes that create therapeutic vulnerability to further inhibition of their paralogs. Here, we report that malic enzyme 2 (ME2) is frequently hemizygously codeleted with SMAD4 in gastric cancer. Its isoenzyme ME1 was upregulated to replenish the intracellular reducing equivalent NADPH and to maintain redox homeostasis. Knockdown of ME1 significantly depleted NADPH, induced high levels of reactive oxygen species (ROS), and ultimately cell apoptosis under oxidative stress conditions, such as glucose starvation and anoikis, in ME2-underexpressed cells. Moreover, ME1 promoted tumor growth, lung metastasis, and peritoneal dissemination of gastric cancer in vivo Intratumoral injection of ME1 siRNA significantly suppressed tumor growth in cell lines and patient-derived xenograft-based models. Mechanistically, ME1 was transcriptionally upregulated by ROS in an ETV4-dependent manner. Overexpression of ME1 was associated with shorter overall and disease-free survival in gastric cancer. Altogether, our results shed light on crucial roles of ME1-mediated production of NADPH in gastric cancer growth and metastasis.Significance: These findings reveal the role of malic enzyme in growth and metastasis.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/8/1972/F1.large.jpg Cancer Res; 78(8); 1972-85. ©2018 AACR.
Highlights
Multifaceted sequencing has revealed an unprecedentedly detailed blueprint for gene amplification or deletion in humanNote: Supplementary data for this article are available at Cancer Research Online.Corrected online July 11, 2019.Y.-X
Homozygous deletion of SMAD4 was frequently identified in nearly one third of pancreatic cancer cases [30], and loss of neighboring housekeeping genes often leads to collateral lethality [4, 6]
Our analysis identified frequent hemizygous deletion of SMAD4 in gastric cancer and concurrent underexpression of malic enzyme 2 (ME2), which leads to high dependency of cancer cells to ME1 in energy stress conditions
Summary
Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). To mine the therapeutic targets with collateral lethality in gastric cancer, we analyzed The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) databases and found that the housekeeping gene ME2 was frequently codeleted or counderexpressed with the tumor suppressor gene SMAD4 in gastric cancer. During energy stress such as glucose deprivation, anchorage-independent growth, and solid tumor formation in vivo, ME1 played essential roles in supplying NADPH for elimination of intracellular ROS when its paralog ME2 was suppressed due to coalteration with SMAD4
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
