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 RNAbinding 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. Ó2016 AACR.

A pan-cancer genome-wide analysis reveals tumour dependencies by induction of nonsense-mediated decay

“…Moreover, we found that stomach adenocarcinoma (STAD) tends to have disproportionately higher number of NMD-elicit mutations and a mutator phenotype that selects for NMD-elicit mutations in LARP4B, EIF5B and PTEN . Although the potential relationship between LARP4B or EIF5B and cancer has been previously reported31323334, the link between these genes and hypermutation was previously unrecognized. It is conceivable that NMD-mediated hypofunction of LARP4B or EIF5B permits the hypermutated cancer cells to cope with a high mutation load by delaying translation.…”

The La and related RNA‐binding proteins (LARPs): structures, functions, and evolving perspectives

“…LARP4B has been found to act as a tumor suppressor and oncogene, possibly dependent on the type of cancer, e.g., solid or blood. LARP4B was identified as a tumor suppressor by a genetic screen in mice and more recently characterized in human glioma cells (for more comprehensive review see Ref ). Overexpression of LARP4B induced apoptosis and mitotic arrest, partially dependent on the La module suggesting that interaction with RNA and its other interacting proteins is important .…”

“…Overexpression of LARP4B induced apoptosis and mitotic arrest, partially dependent on the La module suggesting that interaction with RNA and its other interacting proteins is important . Knockdown of LARP4B in primary mouse astrocytes lacking p53 and Nf1 promoted cell proliferation, tumor size, and invasiveness . In a study of an acute myeloid leukemia mouse model, LARP4B was found to act as an oncogene …”

The Butterfly Effect of RNA Alterations on Transcriptomic Equilibrium

“…Some members of this superfamily, such as LARP1 [169][170][171][172] and LARP6 [173], control the expression of target transcripts and promote the progression of several cancer types. On the other hand, LARP4A [174] and LARP4B [175] are tumor-suppressive RBPs, which inhibit cancer metastasis and growth, respectively.…”