The RNA binding proteins LARP4A and LARP4B promote sarcoma and carcinoma growth and metastasis

TY - JOUR

T1 - The RNA binding proteins LARP4A and LARP4B promote sarcoma and carcinoma growth and metastasis

AU - Grigoriadis, Agamemnon

AU - Conte, Maria R

AU - Coleman, Jennifer

AU - Tattersall, Luke

AU - Yianni, Val

AU - Knight, Laura

AU - Yu, Hongqiang

AU - Hallett, Sadie

AU - Johnson, Philip

AU - Caetano, Ana

AU - Cosstick, Charlie

AU - Ridley, Anne

AU - Gartland, Alison

N1 - Funding Information: The authors thank Prof. Peter Parker (Francis Crick Institute, UK), and Dr. Eric Rahrmann (University of Cambridge, UK) for insightful discussion and critical reading of the article. We thank Drs. Richard Maraia and Sandy Mattijssen (NIH, USA) for the gift of the pCMV2-FLAG-LARP4A plasmid and useful discussions. We are grateful to Dr. Isabel Cruz-Gallardo and Jiazhen Shen for cloning pCB6-GFP-LARP4A and LARP4B plasmids. We thank Dr. Matthias Krause (King's College London) for providing the IX81 microscope set up for the migration experiments, Prof. Anita Grigoriadis (King's College London) for help with the RNAseq experiment, Dr. Magali Williamson (King's College London) for providing us with the PC3 cell line, Prof. Tony Ng (King's College London) for enabling the in vivo studies, and Ms Dhivya Chandrasekaran (King's College London) for technical help with the xenograft experiments. We thank the BRC Flow Cytometry Core and Biological Services Unit at King's College London. This work was supported by a grant from the UK Medical Research Council (MR/N013700/1) awarded to J. Coleman as part of a Doctoral Training Partnership scholarship at King's College London. M.R.C. A.J.R. and A.E.G. conceived the study. J.C. M.R.C and A.E.G. planned and designed experiments. J.C. L.T. L.K. H.Y. S.R.H. P.J. A.J.C. C.C. M.R.C. and A.E.G. performed experiments. V.Y. generated, analyzed, and provided expert consultation on bulk RNAseq analysis. L.T. and A.G. performed the paratibial xenografts and subsequent analysis. M.R.C. and A.E.G. supervised the study. J.C. M.R.C. and A.E.G. wrote and edited the article. The authors declare that they have no competing interests. Funding Information: This work was supported by a grant from the UK Medical Research Council ( MR/N013700/1 ) awarded to J. Coleman as part of a Doctoral Training Partnership scholarship at King’s College London. Publisher Copyright: © 2024

PY - 2024/4/19

Y1 - 2024/4/19

N2 - RNA-binding proteins (RBPs) are emerging as important regulators of cancer pathogenesis. We reveal that the RBPs LARP4A and LARP4B are differentially overexpressed in osteosarcoma and osteosarcoma lung metastases, as well as in prostate cancer. Depletion of LARP4A and LARP4B reduced tumor growth and metastatic spread in xenografts, as well as inhibiting cell proliferation, motility, and migration. Transcriptomic profiling and high-content multiparametric analyses unveiled a central role for LARP4B, but not LARP4A, in regulating cell cycle progression in osteosarcoma and prostate cancer cells, potentially through modulating key cell cycle proteins such as Cyclins B1 and E2, Aurora B, and E2F1. This first systematic comparison between LARP4A and LARP4B assigns new pro-tumorigenic functions to LARP4A and LARP4B in bone and prostate cancer, highlighting their similarities while also indicating distinct functional differences. Uncovering clear biological roles for these paralogous proteins provides new avenues for identifying tissue-specific targets and potential druggable intervention.

AB - RNA-binding proteins (RBPs) are emerging as important regulators of cancer pathogenesis. We reveal that the RBPs LARP4A and LARP4B are differentially overexpressed in osteosarcoma and osteosarcoma lung metastases, as well as in prostate cancer. Depletion of LARP4A and LARP4B reduced tumor growth and metastatic spread in xenografts, as well as inhibiting cell proliferation, motility, and migration. Transcriptomic profiling and high-content multiparametric analyses unveiled a central role for LARP4B, but not LARP4A, in regulating cell cycle progression in osteosarcoma and prostate cancer cells, potentially through modulating key cell cycle proteins such as Cyclins B1 and E2, Aurora B, and E2F1. This first systematic comparison between LARP4A and LARP4B assigns new pro-tumorigenic functions to LARP4A and LARP4B in bone and prostate cancer, highlighting their similarities while also indicating distinct functional differences. Uncovering clear biological roles for these paralogous proteins provides new avenues for identifying tissue-specific targets and potential druggable intervention.

UR - https://www.scopus.com/pages/publications/85188161686

U2 - 10.1016/j.isci.2024.109288

DO - 10.1016/j.isci.2024.109288

M3 - Article

SN - 2589-0042

VL - 27

JO - iScience

JF - iScience

IS - 4

M1 - 109288

ER -