Abstract
Nearly 45% of colorectal cancer (CRC) patients harbor a mutation in their KRAS gene for which, despite many years of research, there are still no targeted therapies available. Protein Arginine Methyltransferase 5 (PRMT5) is a transcription regulator for multiple cellular processes that is currently being tested as a potential target in several cancer types. PRMT5 has been previously shown to be overexpressed in approximately 75% of CRC patient tumor samples, as well as negatively correlated with CRC patient survival. Here, we provide evidence that PRMT5 can act as a surrogate target for mutated KRAS in CRC. Our findings show that PRMT5 expression is upregulated, as well as positively correlated with KRAS expression, in CRC patient datasets. Moreover, our results reveal that PRMT5 is further overexpressed in KRAS mutant CRC cells when compared to KRAS wild type (WT) CRC cells at both the transcriptional and translational levels. Additionally, our data demonstrate that this further overexpression of PRMT5 in the KRAS mutant CRC cells affects an even greater degree of growth inhibition, apoptosis, and cell cycle arrest, following treatment with PRMT5 inhibitor, when compared to the KRAS WT CRC cells. Our research therefore suggests for the first time that PRMT5 and KRAS may crosstalk, and thus, PRMT5 can potentially be used as a surrogate target for mutated KRAS in CRC.
Highlights
Colorectal cancer (CRC) is the second largest cause of cancer death in the USA [1]
Upon analyzing the RNA-Seq data of CRC patients from the TCGA database using the Gene Expression Profiling Interactive Analysis (GEPIA) website, we found that Protein Arginine Methyltransferase 5 (PRMT5) is overexpressed (q < 0.01) in CRC patient tumor samples when compared to normal colon and rectum tissue
Our results show that PRMT5 expression is upregulated, as well as positively correlated with KRAS expression, in CRC patient datasets
Summary
Colorectal cancer (CRC) is the second largest cause of cancer death in the USA [1]. Most cases of CRC take over ten years to fully develop and advance through the adenoma-carcinoma sequence [2,3]. Inactivating mutations of the APC tumor suppressor gene are an early step in the development of CRC and occur in over 70% of colorectal adenomas [2,4]. Additional activating mutations of the KRAS oncogene and inactivating mutations of the TP53 tumor suppressor gene further promote the adenoma-carcinoma sequence [2,4]. A monoclonal antibody that binds to the extracellular domain of EGFR and prevents ligands from binding, was developed as a treatment for CRC [7]. Cetuximab was later determined to be detrimental for CRC patients with a mutated KRAS gene [8,9]
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