Abstract A016: YBX1 is a negative regulator of post-transcriptional program associated with invasion and metastasis in cSCC

Abstract

Abstract Y-box binding protein 1 (YB-1), which is encoded by YBX1 gene, is a multifunctional cold-shock protein that binds both DNA and RNA to orchestrate transcription as well as RNA processing and translation. Recently, we demonstrated that YBX1 is a post-transcriptional effector required for the maintenance of epidermal homeostasis. Although it was well known that YBX1 plays prominent pro-oncogenic roles in malignant transformation and cell invasion in a wide variety of cancers, the role of YBX1 in cutaneous squamous cell carcinoma (SCC) is poorly understood. Here, we report that YBX1 protein level is higher in SCC tumor compared with non-neoplastic skin, but it goes down during tumor progression, in invasive and metastatic states. Indeed, both in vitro and in vivo experiments show that YBX1 acts as an antagonist of SCC progression, inhibiting its migration, invasiveness and metastasis. YBX1 is predominantly found in the cytoplasm of SCC cells. Therefore, we focused on the role of YBX1 as a posttranscriptional regulator and performed an eCLIP-seq (crosslinking immunoprecipitation sequencing) to identify its direct RNA targets. We found that YBX1 binds pro-invasive RNA associated with cell-cell and cell-matrix adhesions. From the integration of eCLIP-seq data with RNA-Bisulfite Seq data, an increased number of m5C modifications was observed to be located within the 3'UTR and CDS of tumor-enriched YBX1 target regions. Upon silencing of YBX1, polysome fractionation analysis revealed that YBX1 KD regulates targets involved in cancer motility, revealing that the loss of function of YBX1 promotes migration and invasion at the post-transcriptional Citation Format: Stefano Sol, Anna Mandinova, Fabiana Boncimino, Kristina Todorova, Emery Di Cicco, Toma Tebaldi, Giorgia Bucciarelli. YBX1 is a negative regulator of post-transcriptional program associated with invasion and metastasis in cSCC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A016.