OMA1 reprograms metabolism under hypoxia to promote colorectal cancer development

Wu, Zhida; Zuo, Meiling; Zeng, Ling; Cui, Kaisa; Liu, Bing; Yan, Chaojun; Chen, Li; Dong, Jun; Shangguan, Fugen; Hu, Wanglai; He, He; Lü, Bin; Song, Zhiyin

doi:10.15252/embr.202050827

Cited by 88 publications

(58 citation statements)

References 65 publications

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“…Under hypoxia, cancer cells could retain survival and stimulate tumor proliferation, migration, and invasion via glycolysis ( Huang and Zong, 2017 ). Wu et al reported that OMA, an ATP-dependent zinc metalloprotease, promotes cancer development by reprogramming metabolic colorectal cancer under hypoxia ( Wu et al, 2021b ). A recent study revealed that hypoxia downregulates the enzymes of pentose phosphate pathway and upregulates the enzymes of glycolysis in tumor and then stimulate tumor migration while inhibiting tumor proliferation ( Kathagen-Buhmann et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of Hypoxia-Related lncRNA Signature as a Prognostic Model for Hepatocellular Carcinoma

Zhou

Zhang

2021

Front. Genet.

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Hepatocellular carcinoma (HCC) is one of the most general malignant tumors. Hypoxia is a critical clinical characteristic and acts as a significant part in the development and cancers’ prognosis. The prognostic value and biological functions of hypoxia-related lncRNAs in hepatocellular carcinoma is little known. Thus, we aim to establish a hypoxia-related lncRNA signature to predict the HCC patients’ survival. First, we extracted the hypoxia-related genes and expression of lncRNAs from the MSigDB and TCGA database, respectively. The co-expression analysis among hypoxia-related mRNAs and lncRNAs was employed to identify hypoxia-related lncRNAs. Then, comprehensive analyses of lncRNAs expression level and survival data were applied to establish the signature. We built a prognostic signature on the foundation of the three differently expressed hypoxia-related lncRNAs. Kaplan-Meier curves indicated the low-risk group is associated with better survival. The 1−, 3−, and 5 years AUC values of the signature were 0.805, 0.672 and 0.63 respectively. The test set performed consistent outcomes. A nomogram was built grounded on the risk score and clinicopathological features. GSEA showed the immune-related pathways in high-risk group, while metabolism-related pathways in low-risk group. Besides, we found this model was correlated with the clinical features, tumor immune cell infiltration, immune checkpoints, and m6A-related genes. Finally, a novel signature based on hypoxia-related lncRNAs was established and validated for predicting HCC patients’ survival and may offer some useful information for immunotherapies.

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Section: Discussionmentioning

confidence: 99%

Identification and Validation of Hypoxia-Related lncRNA Signature as a Prognostic Model for Hepatocellular Carcinoma

Zhou

Zhang

2021

Front. Genet.

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“…For example, cancer survival correlated with OMA1 gene expression levels in multiple studies. 9,58,59 The protooncogene MYC could thereby be responsible for OMA1's differential expression in tumors. 9 Another study placed OMA1 downstream of tumor protein p53.…”

Section: Discussionmentioning

confidence: 99%

OMA1 High-throughput Screen Reveals Protease Activation by Kinase Inhibitors

Alavi¹

2021

Preprint

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Mitochondrial proteases are interesting but challenging drug targets for multifactorial diseases, such as neurodegeneration and cancer. The mitochondrial inner membrane protease OMA1 is a bona fide drug target for heart failure supported by data from human linkage analysis and animal disease models, but presumably relevant for more indications. OMA1 acts at the intersection of energy metabolism and stress signaling. The protease cleaves the structural protein OPA1, which organizes the cristae, as well as the signaling peptide DELE1, which can stimulate the integrated stress response. OMA1 shows little activity under physiological conditions but hydrolyzes OPA1 in mitochondria destined for mitophagy and during apoptosis. Little is known about OMA1, its structure has not been solved, let alone its context-dependent regulation. Autocatalytic processing and the lack of OMA1 inhibitors are thereby creating the biggest roadblocks. This study introduces a scalable, cellular OMA1 protease assay suitable for high-throughput drug screening. The assay utilizes an engineered luciferase targeted to the inner membrane as artificial OMA1 substrate, whereby the reporter signal inversely correlates to OMA1 activity. Testing different screening protocols and sampling different compound collections validated the reporter and demonstrated that both OMA1 activators as well as OMA1 inhibitors can be identified with the assay. Ten kinase-targeted cancer drugs triggered OMA1 in the assays, which suggests, considering cardiotoxicity as a rather common side-effect of this class of drugs, cross-reactivity with the OMA1 pathway.

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“…On the contrary, OMA1 knockout is known to suppress CRC development. Upon activation by hypoxia, OMA1 increases mitochondrial ROS to stabilize HIF-1α, thus promoting glycolysis and suppressing OXPHOS in CRC cells [ 95 ]. These results suggest the crucial role of OMA1 in HIF-1α-mediated CRC development and a high potential as a target for CRC therapy.…”

Section: Associated Mitochondrial Mutations and Dysfunctionsmentioning

confidence: 99%

The Role of Mitochondria Dysfunction in Inflammatory Bowel Diseases and Colorectal Cancer

Kłos

Dabravolski

2021

IJMS

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Inflammatory bowel disease (IBD) is one of the leading gut chronic inflammation disorders, especially prevalent in Western countries. Recent research suggests that mitochondria play a crucial role in IBD development and progression to the more severe disease—colorectal cancer (CRC). In this review, we focus on the role of mitochondrial mutations and dysfunctions in IBD and CRC. In addition, main mitochondria-related molecular pathways involved in IBD to CRC transition are discussed. Additionally, recent publications dedicated to mitochondria-targeted therapeutic approaches to cure IBD and prevent CRC progression are discussed.

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OMA1 reprograms metabolism under hypoxia to promote colorectal cancer development

Cited by 88 publications

References 65 publications

Identification and Validation of Hypoxia-Related lncRNA Signature as a Prognostic Model for Hepatocellular Carcinoma

Identification and Validation of Hypoxia-Related lncRNA Signature as a Prognostic Model for Hepatocellular Carcinoma

OMA1 High-throughput Screen Reveals Protease Activation by Kinase Inhibitors

The Role of Mitochondria Dysfunction in Inflammatory Bowel Diseases and Colorectal Cancer

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