Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer

Oran, Amanda; Adams, Clare M.; Zhang, Xiao Yong; Gennaro, Victoria; Pfeiffer, Harla K.; Mellert, Hestia; Seidel, Hans E.; Mascioli, Kirsten; Kaplan, Jordan; Gaballa, Mahmoud R.; Shen, Chen; Rigoutsos, Isidore; King, Michael P.; Cotney, Justin; Arnold, Jamie J.; Sharma, Suresh D.; Martinez‐Outschoorn, Ubaldo; Vakoc, Christopher R.; Chodosh, Lewis A.; Thompson, James E.; Bradner, James E.; Cameron, Craig Ε.; Shadel, Gerald S.; Eischen, Christine M.; McMahon, Steven B.

doi:10.18632/oncotarget.11718

Cited by 33 publications

(41 citation statements)

References 79 publications

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“…Elimination of either molecule in mice aggravated the recovery from I/R injury. Although the PAX8-driven, tubule-specific gene excision removed these molecules only from a limited subset of kidney cells, RNA sequencing of whole kidney lysates revealed extensive mitochondrial and metabolic changes in comparison to control mice exposed to the same injury, supporting recent observations that both CXCL12/CXCR4 and MYC signaling can control mitochondrial gene expression, and contribute to the adaptive responses after I/R injury 43 , 44 . Tubule-specific loss of Cxcl12 and Myc also significantly reduced retinol metabolic processes, providing the rational to use retinoic acid to antagonize these signaling defects.…”

Section: Discussionsupporting

confidence: 67%

CXCL12 and MYC control energy metabolism to support adaptive responses after kidney injury

et al. 2018

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Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos. Gene expression profiles between these two developmental stages identify cxcl12a and myca as candidates involved in the repair process. Zebrafish embryos with cxcl12a, cxcr4b, or myca deficiency display repair abnormalities, confirming their role in response to injury. In mice with a kidney-specific knockout, Cxcl12 and Myc gene deletions suppress mitochondrial metabolism and glycolysis, and delay the recovery after ischemia/reperfusion injury. Probing these observations in zebrafish reveal that inhibition of glycolysis slows fast migrating cells and delays the repair after injury, but does not affect the slow cell movements during kidney development. Our findings demonstrate that Cxcl12 and Myc facilitate glycolysis to promote fast migratory responses during development and repair, and potentially also during tumor invasion and metastasis.

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Section: Discussionsupporting

confidence: 67%

CXCL12 and MYC control energy metabolism to support adaptive responses after kidney injury

et al. 2018

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“…Here, the finding that remodeling of mitochondrial functions is the most common alteration downstream of a ubiquitous oncogene, i.e., Myc (2), demonstrates that mitochondria play a general role in cancer and constitute a hallmark of Myc-driven tumors. This conclusion is in line with an expanding role of Myc in affecting mitochondrial biology for tumor maintenance, including regulation of oxidative phosphorylation gene expression (8), reprogramming of glutamine metabolism (33), and fatty acid oxidation (34). However, the importance of mitochondrial dynamics (11), in particular subcellular mitochondrial trafficking (23), in Myc regulation of tumor cell movements has not been previously reported, and in fact, changes in mitochondrial biogenesis (35) and fusion/fission balance (36) downstream of Myc have rather been linked to inhibition of YAP/TAZ oncogenes (11).…”

Section: Discussionsupporting

confidence: 73%

Myc Regulation of a Mitochondrial Trafficking Network Mediates Tumor Cell Invasion and Metastasis

Agarwal

Altman

Seo

et al. 2019

Molecular and Cellular Biology

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The Myc gene is a universal oncogene that promotes aggressive cancer, but its role in metastasis has remained elusive. Here, we show that Myc transcriptionally controls a gene network of subcellular mitochondrial trafficking that includes the atypical mitochondrial GTPases RHOT1 and RHOT2, the adapter protein TRAK2, the anterograde motor Kif5B, and an effector of mitochondrial fission, Drp1. Interference with this pathway deregulates mitochondrial dynamics, shuts off subcellular organelle movements, and prevents the recruitment of mitochondria to the cortical cytoskeleton of tumor cells. In turn, this inhibits tumor chemotaxis, blocks cell invasion, and prevents metastatic spreading in preclinical models. Therefore, Myc regulation of mitochondrial trafficking enables tumor cell motility and metastasis.

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“…Genes encoding components of the mitochondrial ribosome were coordinately activated during lymphomagenesis (19) and were critical for tumor maintenance in E-myc transgenic mice (16). In line with these genetic data, pharmacological inhibition of the mitochondrial ribosome with tigecycline was synthetically lethal with MYC activation, impaired tumor cell survival in vitro, and extended life span in lymphoma-bearing mice (16,17). Here, we present preclinical data showing that venetoclax and tigecycline synergize in the treatment of MYC/BCL2 DHL, allowing tumor eradication in xenografted mice.…”

Section: Introductionmentioning

confidence: 86%

“…On this basis, we reasoned that compounds that exacerbate MYC-induced apoptosis would be likely to cooperate with venetoclax in killing DHL cells. A candidate compound was tigecycline (16,17), a broad-spectrum antibacterial agent with documented cytotoxicity against diverse cancer cell types, most likely owing to its inhibitory effect on mitochondrial translation (18).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic synergy between tigecycline and venetoclax in a preclinical model of MYC / BCL2 double-hit B cell lymphoma

et al. 2018

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High-grade B cell lymphomas with concurrent activation of the and oncogenes, also known as double-hit lymphomas (DHL), show dismal prognosis with current therapies. activation sensitizes cells to inhibition of mitochondrial translation by the antibiotic tigecycline, and treatment with this compound provides a therapeutic window in a mouse model of-driven lymphoma. We now addressed the utility of this antibiotic for treatment of DHL. activation in mouse Eμ- lymphomas antagonized tigecycline-induced cell death, which was specifically restored by combined treatment with the BCL2 inhibitor venetoclax. In line with these findings, tigecycline and two related antibiotics, tetracycline and doxycycline, synergized with venetoclax in killing human DHL cells. Treatment of mice engrafted with either DHL cell lines or a patient-derived xenograft revealed strong antitumoral effects of the tigecycline/venetoclax combination, including long-term tumor eradication with one of the cell lines. This drug combination also had the potential to cooperate with rituximab, a component of current front-line regimens. Venetoclax and tigecycline are currently in the clinic with distinct indications: Our preclinical results warrant the repurposing of these drugs for combinatorial treatment of DHL.

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Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer

Cited by 33 publications

References 79 publications

CXCL12 and MYC control energy metabolism to support adaptive responses after kidney injury

CXCL12 and MYC control energy metabolism to support adaptive responses after kidney injury

Myc Regulation of a Mitochondrial Trafficking Network Mediates Tumor Cell Invasion and Metastasis

Therapeutic synergy between tigecycline and venetoclax in a preclinical model of MYC / BCL2 double-hit B cell lymphoma

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