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

Abstract

Despite ubiquitous activation in human cancer, essential downstream effector pathways of the MYC transcription factor have been difficult to define and target. Using a structure/function-based approach, we identified the mitochondrial RNA polymerase (POLRMT) locus as a critical downstream target of MYC. The multifunctional POLRMT enzyme controls mitochondrial gene expression, a process required both for mitochondrial function and mitochondrial biogenesis. We further demonstrate that inhibition of this newly defined MYC effector pathway causes robust and selective tumor cell apoptosis, via an acute, checkpoint-like mechanism linked to aberrant electron transport chain complex assembly and mitochondrial reactive oxygen species (ROS) production. Fortuitously, MYC-dependent tumor cell death can be induced by inhibiting the mitochondrial gene expression pathway using a variety of strategies, including treatment with FDA-approved antibiotics. In vivo studies using a mouse model of Burkitt's Lymphoma provide pre-clinical evidence that these antibiotics can successfully block progression of MYC-dependent tumors.

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

“…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.…”

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

“…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).…”

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

“…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.…”

“…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).…”