Ponnurangam, S. | Search bioRxiv

bioRxiv2022

Doublecortin like kinase 1 is a target in squamous cell carcinoma

Doublecortin like kinase 1 (DCLK1) plays a crucial role in several cancers including colon and pancreatic adenocarcinomas. However, its role in squamous cell carcinoma (SCC) remains unknown. To this end, we examined DCLK1 expression in head and neck squamous cell carcinoma (HNSCC) and anal squamous cell carcinoma (ASCC). We found that DCLK1 is elevated in patient SCC tissue, which correlated with cancer progression and poorer overall survival. Furthermore, DCLK1 expression is significantly elevated in HPV negative cancer tissues, which are typically aggressive with poor responses to radiation therapy. To understand the role of DCLK1 in tumorigenesis, we used specific shRNA to suppress DCLK1 expression. This significantly reduced tumor growth, spheroid formation, and migration of HNSCC cancer cells. To further the translational relevance of our studies, we sought to identify a selective DCLK1 inhibitor. Current attempts to target DCLK1 using pharmacologic approaches have relied on non-specific suppression of DCLK1 kinase activity. Here, we demonstrate that DiFiD [3,5-bis (2,4-difluorobenzylidene)-4-piperidone] binds to DCLK1 with high selectivity. Moreover, DiFiD mediated suppression of DCLK1 led to G2/M arrest and apoptosis and significantly suppressed tumor growth of HNSCC xenografts and ASCC patient derived xenografts, supporting that DCLK1 is critical for SCC growth.

cancer biology↗

bioRxiv2021

RNA binding protein RBM3 augments kissing loop formation with lncRNAs to enhance translational control

It is becoming apparent that translational regulation involves the coordinated actions of RNA binding proteins (RBPs) and non-coding RNAs. For efficient translation, mRNA needs to be circularized, which is catalyzed by RNA binding proteins and translation factors. However, the role of lncRNAs in the process is not yet defined. We first performed RNA-seq and RNA- immunoprecipitation coupled-Seq and identified LSAMP-3 and Flii-1. Moreover, modeling studies suggest enhanced kissing loop interactions including of transcripts that encode angiogenesis and epithelial mesenchymal transition. While intestinal epithelial cell specific RBM3 transgenic mice showed increased LSAMP-3 and Flii-1, this was reduced in knockout mice. Also, RBM3 overexpression increased tumor xenograft growth, this was suppressed by knockdown of the lncRNAs. Also, knockdown of endogenous RBM3 reduced lncRNA levels and tumor xenograft growth. In addition, it reduced colitis-associated cancers. We propose that RBPs such as RBM3 mediate their function through regulatory lncRNAs that enable circularization to control translation.

cancer biology↗