MYC is downregulated by a mitochondrial checkpoint mechanism

Zhang, Xiaonan; Mofers, Arjan; Olofsson, Maria Hägg; Guo, Jing; Linder, Stig; D’Arcy, Pádraig

doi:10.18632/oncotarget.21653

Cited by 13 publications

(14 citation statements)

References 54 publications

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“…Our finding is the first to show the link between OxPhos inhibition and YAP Ser94 phosphorylation. ClpP agonists and other mitochondria-targeting drugs downregulated Myc, and this is also shown in recent reports(48-50). Myc stimulates mitochondrial biosynthesis, including glutamine-proline axis(51-53), therefore downregulation of Myc by ClpP agonists may lead to further mitochondrial dysfunction(39,52).…”

Section: Discussionsupporting

confidence: 79%

Mitochondrial Matrix Protease ClpP Agonists inhibit Cancer Stem Cell Function in Breast Cancer Cells by Disrupting Mitochondrial Homeostasis

Greer¹,

Hernandez²,

Fennell

et al. 2022

Preprint

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Mitochondria are multifaceted organelles which are important for bioenergetics, biosynthesis and signaling in metazoans. Mitochondrial functions are frequently altered in cancer to promote both the energy and the necessary metabolic intermediates for biosynthesis required for tumor growth. Cancer stem cells (CSCs) contribute to chemotherapy resistance, relapse, and metastasis. Recent studies have shown that while non-stem, bulk cancer cells utilize glycolysis, breast CSCs are more dependent on oxidative phosphorylation (OxPhos) and therefore targeting mitochondria may inhibit CSC function. We previously reported that small molecule ONC201, which is an agonist for the mitochondrial caseinolytic protease (ClpP), induces mitochondrial dysfunction in breast cancer cells. In this study, we report that ClpP agonists inhibit breast cancer CSC function in vitro and in vivo. Mechanistically, we found that OxPhos inhibition downregulates multiple pathways required for CSC function, such as the mevalonate pathway, YAP, Myc, and the HIF pathway. ClpP agonists showed significantly greater inhibitory effect on CSC functions compared with other mitochondria-targeting drugs. Further studies showed that ClpP agonists deplete NAD(P)+ and NAD(P)H and induce redox imbalance, and dysregulate one-carbon metabolism and proline biosynthesis. Downregulation of these pathways by ClpP agonists further contribute to the inhibition of CSC function. In conclusion, ClpP agonists inhibit breast CSC functions by disrupting mitochondrial homeostasis in breast cancer cells and inhibiting multiple pathways critical to CSC function.

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Section: Discussionsupporting

confidence: 79%

Mitochondrial Matrix Protease ClpP Agonists inhibit Cancer Stem Cell Function in Breast Cancer Cells by Disrupting Mitochondrial Homeostasis

Greer¹,

Hernandez²,

Fennell

et al. 2022

Preprint

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“…Succinate has recently been discovered to drive thermogenesis in brown fat tissues (Mills et al, 2018). Mitochondrial ROS regulates myc signaling (Zhang et al, 2017), while mitochondrial (E) Endoplasmic reticulum stress rescue was measured in bcs1l R73C/F368I fibroblasts. Representative blots are shown at left, while the quantification is reported at right (n = 3; means ± SEMs).…”

Section: Discussionmentioning

confidence: 99%

Impaired Mitochondrial ATP Production Downregulates Wnt Signaling via ER Stress Induction

et al. 2019

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“…Interestingly, it has been shown that the inhibition of mitochondrion function decreases the mRNA level of Myc through let-7/miR-34a signaling pathway. 23 Here, we demonstrated that FASTKD2 transcriptionally upregulated the c-Myc expression in pancreatic cancer. Furthermore, we verified that FASTKD2 interacted with BRD4 to regulate c-Myc expression.…”

Section: Discussionmentioning

confidence: 66%

FASTKD2 promotes cancer cell progression through upregulating Myc expression in pancreatic ductal adenocarcinoma

Fang

Zhang

et al. 2019

J of Cellular Biochemistry

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal cancers of the digestive system. Despite the development of novel therapeutic methods, including chemotherapy, radiotherapy, and molecular targeted therapy, the incidence rate of PDAC is almost equal to the mortality rate with 5-year overall survival rate less than 5%. Kras mutation is found in 95% of patient with PDAC specimens, but targeting Kras mutation do not benefit patients with pancreatic cancer in preclinical trials. c-Myc is one of the main effector molecules of the Kras signaling pathway. In this study, we found that dysregulation of FAST kinase-domain-containing protein 2 (FASTKD2) resulted in the poor prognosis of patients with PDAC. Then, we showed that FASTKD2 promoted pancreatic cancer cell proliferation and invasion. Importantly, we demonstrated that c-Myc was transcriptionally increased by FASTKD2/BRD4 axis and responsible for FASTKD2-mediated tumor growth and invasion in pancreatic cancer cells. Collectively, this study uncovered that FASTKD2 promoted cancer cell progression through upregulating Myc expression in pancreatic cancer. FASTKD2 might be a potential target for pancreatic cancer therapy.

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MYC is downregulated by a mitochondrial checkpoint mechanism

Cited by 13 publications

References 54 publications

Mitochondrial Matrix Protease ClpP Agonists inhibit Cancer Stem Cell Function in Breast Cancer Cells by Disrupting Mitochondrial Homeostasis

Mitochondrial Matrix Protease ClpP Agonists inhibit Cancer Stem Cell Function in Breast Cancer Cells by Disrupting Mitochondrial Homeostasis

Impaired Mitochondrial ATP Production Downregulates Wnt Signaling via ER Stress Induction

FASTKD2 promotes cancer cell progression through upregulating Myc expression in pancreatic ductal adenocarcinoma

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