Coordinated post-transcriptional control of oncogene-induced senescence by UNR/CSDE1

Abstract

Highlights d CSDE1 is a tumor suppressor in primary mouse keratinocytes d CSDE1 promotes oncogene-induced senescence (OIS) d CSDE1 coordinates the two branches of OIS: proliferation and the SASP d CSDE1 enhances SASP factor mRNA stability and represses Ybx1 mRNA translation

CSDE1: a versatile regulator of gene expression in cancer

“…CSDE1 binding specificity is somewhat relaxed. Initial in vitro SELEX experiments indicated a purine-rich motif with a core of AAGUA/G or AACG, which has been confirmed in Bind-N-Seq experiments and in vivo iCLIP studies ( 47 , 49 , 63 , 64 ) (Figure 3A ). While these motifs might be present frequently in the transcriptome, a meta-analysis reveals a predilection for CSDE1 binding near the start codon and following the termination codon of the open reading frame, suggesting that additional features contribute to RNA-binding specificity (Figure 3B ).…”

“…found CSDE1 loss-of-function mutations as drivers of neuroendocrine tumors with a Wnt-altered phenotype, indicating that CSDE1 is a suppressor of this tumor type ( 48 ). CSDE1 also behaves as a tumor suppressor in squamous cell carcinoma, where it promotes oncogene-induced senescence by repressing the synthesis of YBX1 and enhancing the stability of mRNAs encoding senescence-associated secretory phenotype (SASP) factors ( 49 ). In addition, tumor suppressor roles of CSDE1 can be inferred from studies in glioma, where CSDE1 was identified as the target of the drug clofoctol ( 50 ).…”

“…( B ) Metaprofiles of CSDE1 binding to its targets in melanoma and PMK. iCLIP peak counts from references ( 47 ) and ( 49 ) were averaged across replicates and scaled for comparison. ( C ) Venn diagram comparing CSDE1 RNA targets in mouse cardiac endothelial cells (MCEC) ( 74 ), melanoma ( 47 ) and either proliferating or senescent PMK ( 49 ).…”

“…In order to obtain a global view of CSDE1 targets, we compared the transcripts bound to endogenous CSDE1 in three large-scale studies performed in melanoma cells, primary mouse keratinocytes (PMK, either under proliferating or senescent conditions), and mouse cardiac endothelial cells (MCEC) ( 47 , 49 , 74 ). Although thousands of transcripts were bound by CSDE1 in each condition, a common set of 229 targets was found, supporting the prevalent context-specific nature of CSDE1 interactions with RNA (Figure 3C ).…”

RNA-Binding Proteins Regulate Post-Transcriptional Responses to TGF-β to Coordinate Function and Mesenchymal Activation of Murine Endothelial Cells

“…45,46 Csde1 is also known to act as both a promoter and suppressor of oncogenesis in a contextdependent manner and has been shown to directly interact with TGF-β1 RNA and other related RNAs in cancer cells to influence metastasis and migration. 29,47,48 Previous data showed that Csde1 preferentially binds to the 5ʹ UTR of selective RNA targets, allowing it to impact early translational elongation. 47 We confirmed increased 5´UTR binding for endothelial Csde1 specifically on TGF-β stimulation, although we did not further investigate this mode of action in our study.…”