The RNA helicase DDX5 supports mitochondrial function in small cell lung cancer

Zheng Xing,Matthew P Russon,Sagar M Utturkar,Elizabeth J Tran

doi:10.1074/jbc.ra120.012600

Zheng Xing, Matthew P Russon + Show 2 more

Open Access

https://doi.org/10.1074/jbc.ra120.012600

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Abstract

DEAD-box helicase 5 (DDX5) is a founding member of the DEAD-box RNA helicase family, a group of enzymes that regulate ribonucleoprotein formation and function in every aspect of RNA metabolism, ranging from synthesis to decay. Our laboratory previously found that DDX5 is involved in energy homeostasis, a process that is altered in many cancers. Small cell lung cancer (SCLC) is an understudied cancer type for which effective treatments are currently unavailable. Using an array of methods, including short hairpin RNA-mediated gene silencing, RNA and ChIP sequencing analyses, and metabolite profiling, we show here that DDX5 is overexpressed in SCLC cell lines and that its down-regulation results in various metabolic and cellular alterations. Depletion of DDX5 resulted in reduced growth and mitochondrial dysfunction in the chemoresistant SCLC cell line H69AR. The latter was evidenced by down-regulation of genes involved in oxidative phosphorylation and by impaired oxygen consumption. Interestingly, DDX5 depletion specifically reduced intracellular succinate, a TCA cycle intermediate that serves as a direct electron donor to mitochondrial complex II. We propose that the oncogenic role of DDX5, at least in part, manifests as up-regulation of respiration supporting the energy demands of cancer cells.

Highlights

The DEAD-box RNA helicase DDX5 is overexpressed in multiple types of cancers in which its expression is necessary for cell proliferation and tumor growth [1,2,3,4]
DDX5 is an RNA helicase whose overexpression is correlated with multiple cancer types, including breast, colon, and prostate [23], and is associated with resistance to therapeutics in the non– small cell lung cancer cell line H1299 [24]
DEAD-box RNA helicases are the largest class of enzymes in the RNA helicase family, acting as nonprocessive, ATP-dependent RNA-binding proteins, whose activity can be coupled to remodeling of secondary structure and/or RNA–protein complexes [32]

Summary

Introduction

The DEAD-box RNA helicase DDX5 is overexpressed in multiple types of cancers in which its expression is necessary for cell proliferation and tumor growth [1,2,3,4]. Depletion of DDX5 in mammalian cells or deletion of DBP2 in S. cerevisiae lead to differential expression of metabolic genes [13, 14] and alteration of glycolysis and mitochondrial respiration activity [6, 15]. We show that DDX5 depletion leads to growth defects and global changes of gene expression in drugresistant SCLC cells.

Results

Conclusion