The RNA‐binding protein LARP4 regulates cancer cell migration and invasion

Shailaja Seetharaman,Anne J. Ridley,Ella Flemyng,Maria R. Conte,Jiazhen Shen

doi:10.1002/cm.21336

Abstract

LARP4 is a La‐related RNA‐binding protein implicated in regulating mRNA translation, which interacts with poly(A)‐binding protein (PABP). We previously identified LARP4 in an RNAi screen as one of several genes that regulate the shape of PC3 prostate cancer cells. Here we show that LARP4 depletion induces cell elongation in PC3 cells and MDA‐MB‐231 breast cancer cells. LARP4 depletion increases cell migration and invasion, as well as inducing invasive cell protrusions in 3D Matrigel. Conversely, LARP4 over‐expression reduces cell elongation and increases cell circularity. LARP4 mutations are found in a variety of cancers. Introduction of some of these cancer‐associated mutations, including a truncation mutant, into LARP4 enhances its effects on cell morphology. The truncation mutant shows enhanced interaction with PABP. We propose that LARP4 inhibits migration and invasion of cancer cells, and that some cancer‐associated mutations stimulate these effects of LARP4. © 2016 The Authors. Cytoskeleton Published by Wiley Periodicals, Inc.

Highlights

Cell migration is essential for animal development and tissue repair, and contributes to human diseases including cancer progression [Friedl and Gilmour, 2009; Ridley, 2015]
We demonstrate that La-related protein 4 (LARP4) depletion induces cell elongation and increases cell migration speed in both PC3 prostate cancer cells and MDA-MB-231 breast cancer cells
To study the effects of LARP4 on cell morphology, LARP4 was depleted by siRNA-mediated knockdown in MDAMB-231 breast cancer cells and PC3 prostate cancer cells, both of which migrate predominantly as single cells and do not express the epithelial cell-cell adhesion molecule Ecadherin [Neve et al, 2006; Valderrama et al, 2012]

Summary

Introduction

Cell migration is essential for animal development and tissue repair, and contributes to human diseases including cancer progression [Friedl and Gilmour, 2009; Ridley, 2015]. Genome-wide RNA interference (RNAi) screens have been used to identify putative actin regulators that are not well-studied for their role in cytoskeletal dynamics. 99 genes that affected migration of the distal tip cells during gonadogenesis were identified in an RNAi screen in Caenorhabditis elegans [Cram et al, 2006]. La-related protein 4 (LARP4) was identified as one of several novel regulators of prostate cancer cell morphology [Bai et al, 2011] based on a previous genome-wide RNAi screen in Drosophila melanogaster [Rohn et al, 2011]. Depletion of LARP4 in PC3 prostate cancer cells resulted in cell elongation, a phenotype similar to that of depleting several other proteins including the Rho GTPases RhoA, RhoU and the formin Dia. There was an increase in long thin protrusions containing microtubules in LARP4-depleted cells [Bai et al, 2011]

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Conclusion