eIF4A2 is a regulator of hypoxic translation and colorectal tumour cell survival.


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Hannah Bolland1,Alan McIntyre1,Abdol Shams-Nateri1,Cleo Bishop2,Andrew Silver2
1University of Nottingham,2Blizzard Institute Barts and the London School of Medicine and Dentistry

Abstract

Background

Colorectal cancer kills more than half a million people a year worldwide. Hypoxia (low oxygen) is associated with increased chemotherapy and radiotherapy resistance. 1 in 3 colorectal tumours contain regions of low oxygen. Under hypoxic conditions components of the protein synthesis machinery undergo an adaptive change as do the translational efficiencies of a subset of pro-survival mRNAs. eIF4A2, an RNA helicase is differentially expressed in a variety of cancers. We hypothesised that eIF4A2 played a role in normoxic and hypoxic colon tumour cell survival through its regulation of proteins required for hypoxic survival.

Method

Using a panel of colorectal cancer cell lines we assessed hypoxic regulation of eIF4A2 and its role in survival and cell viability in 2D and 3D spheroid cultures and in on-going in vivo experiments using inducible shRNA eIF4A2 knockdowns. RNA-seq was used to identify eIF4A2 regulated transcripts.

Results

eIF4A2 was significantly upregulated by hypoxia at the protein and RNA level under control of HIF1α. Knockdown of eIF4A2 significantly reduced cell survival and proliferation in 2D and 3D spheroid cultures, and we identified increased apoptosis and necrosis in the hypoxic core of the spheroids. RIP-seq identified a number of key hypoxia pro-survival proteins are eIF4A2 dependently translated.  

Conclusion

eIF4A2 is required for hypoxic tumour cell survival in colorectal cancer. This highlights the value of the development of small molecule inhibitors that specifically target eIF4A2 to target the therapy resistant hypoxic tumour microenvironment.