Pleotropic role of RNA binding protein CELF2 in autophagy induction

Abstract

We previously reported that ionizing radiation (IR) mediates cell death through the induction of CUGBP elav-like family member 2 (CELF2), a tumor suppressor. CELF2 is an RNA binding protein that modulates mRNA stability and translation. Since IR induces autophagy, we hypothesized that CELF2 regulates autophagy-mediated colorectal cancer (CRC) cell death. For clinical relevance, we determined CELF2 levels in The Cancer Genome Atlas (TCGA). Role of CELF2 in radiation response was carried out in CRC cell lines by immunoblotting, immunofluorescence, autophagic vacuole analyses, RNA stability assay, quantitative polymerase chain reaction and electron microscopy. In vivo studies were performed in a xenograft tumor model. TCGA analyses demonstrated that compared to normal tissue, CELF2 is expressed at significantly lower levels in CRC, and is associated with better overall 5-year survival in patients receiving radiation. Mechanistically, CELF2 increased levels of critical components of the autophagy cascade including Beclin-1, ATG5, and ATG12 by modulating mRNA stability. CELF2 also increased autophagic flux in CRC. IR significantly induced autophagy in CRC which correlates with increased levels of CELF2 and autophagy associated proteins. Silencing CELF2 with siRNA, mitigated IR induced autophagy. Moreover, knockdown of CELF2 in vivo conferred tumor resistance to IR. These studies elucidate an unrecognized role for CELF2 in inducing autophagy and potentiating the effects of radiotherapy in CRC.

Integrated Analysis of the Functions and Prognostic Values of RNA Binding Proteins in Lung Squamous Cell Carcinoma

“…RNA binding proteins (RBPs) are proteins that interact with various types of RNA and are ubiquitously expressed in cells (Masuda and Kuwano, 2019;New et al, 2019;Otsuka et al, 2019). A total of 1542 RBPs have been identified by highthroughput screening in human cells, representing 7.5% of all protein coding genes (Gerstberger et al, 2014).…”

Identification of Autophagy-Associated Biomarkers and Corresponding Regulatory Factors in the Progression of Colorectal Cancer

“…In this study, we have revealed the expression signatures of autophagy genes regulated by multiple factors, which include TF, miRNA, promoter methylation, and CNV. Some studies have demonstrated that RNA binding proteins as TFs play a key role in the development and function of CRC (New et al, 2019). RNA binding proteins regulate the expression of thousands of transcripts and are crucial for the regulation of CRC cellular processes, such as RNA splicing, modifications, transport, and translation (Kudinov et al, 2017;Chatterji and Rustgi, 2018).…”

“…The TF that targeted the autophagy genes were acquired from ChIPBase 5 (Zhou et al, 2017). The 2949 RBP were downloaded from the EuRBPDB 6 (New et al, 2019). The miRNA-gene targeted interaction was formed through the integration of miRecords 7 (Xiao et al, 2009), DIANA-TarBase 8 (Vlachos et al, 2015), and miRTarBase 9 (Chou et al, 2018) databases.…”

“…In addition, RNA-binding proteins (RBP) play a key role in many processes as TF, including cellular differentiation, autophagy, apoptosis, and DNA repair (Gerstberger et al, 2014;Williams et al, 2019). For instance, some researches have shown that CELF2 RNA-binding protein regulates autophagy-mediated CRC cell death (New et al, 2019). Furthermore, Kudinov AE et al found that MSI2 RNA-binding protein as a regulator of progenitor cell is elevated in colorectal adenocarcinomas and that its loss of function inhibits the growth of CRC cells (New et al, 2019).…”

“…For instance, some researches have shown that CELF2 RNA-binding protein regulates autophagy-mediated CRC cell death (New et al, 2019). Furthermore, Kudinov AE et al found that MSI2 RNA-binding protein as a regulator of progenitor cell is elevated in colorectal adenocarcinomas and that its loss of function inhibits the growth of CRC cells (New et al, 2019). In the past decade, autophagy as a new therapeutics has attracted extensive attention.…”