title: Identification of RNA-Binding Protein LARP4B as a Tumor Suppressor in Glioma.
abstract: Transposon-based insertional mutagenesis is a valuable method for conducting unbiased forward genetic screens to identify cancer genes in mice. We used this system to elucidate factors involved in the malignant transformation of neural stem cells into glioma-initiating cells. We identified an RNA-binding protein, La-related protein 4b (LARP4B), as a candidate tumor-suppressor gene in glioma. LARP4B expression was consistently decreased in human glioma stem cells and cell lines compared with normal neural stem cells. Moreover, heterozygous deletion of LARP4B was detected in nearly 80% of glioblastomas in The Cancer Genome Atlas database. LARP4B loss was also associated with low expression and poor patient survival. Overexpression of LARP4B in glioma cell lines strongly inhibited proliferation by inducing mitotic arrest and apoptosis in four of six lines as well as in two patient-derived glioma stem cell populations. The expression levels of CDKN1A and BAX were also upregulated upon LARP4B overexpression, and the growth-inhibitory effects were partially dependent on p53 (TP53) activity in cells expressing wild-type, but not mutant, p53. We further found that the La module, which is responsible for the RNA chaperone activity of LARP4B, was important for the growth-suppressive effect and was associated with BAX mRNA. Finally, LARP4B depletion in p53 and Nf1-deficient mouse primary astrocytes promoted cell proliferation and led to increased tumor size and invasiveness in xenograft and orthotopic models. These data provide strong evidence that LARP4B serves as a tumor-suppressor gene in glioma, encouraging further exploration of the RNA targets potentially involved in LARP4B-mediatd growth inhibition. Cancer Res; 76(8); 2254-64. ©2016 AACR.
authors.affiliation: Division of Molecular and Developmental Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: Koso
authors.affiliation: Division of Molecular and Developmental Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hungtsung
authors.initials: H
authors.lastname: Yi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Paul
authors.initials: P
authors.lastname: Sheridan
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Division of Innovative Cancer Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ino
authors.affiliation: Division of Innovative Cancer Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Todo
authors.affiliation: Division of Molecular and Developmental Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. sumiko@ims.u-tokyo.ac.jp.
authors.forename: Sumiko
authors.initials: S
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D017209:Apoptosis; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis; D011485:Protein Binding; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000097585:SS-B Antigen
chemical_list: D001324:Autoantigens; D012261:Ribonucleoproteins; D051028:bcl-2-Associated X Protein; D000097585:SS-B Antigen; C494826:BAX protein, human