Abstract 3369: PRMT5 is positively correlated with and interacts with the ERK1/2 & PI3K Pathways in CRC
Authors: Shifteh David , Sapir Tzuriel , Pahmer Moshe , Goel Sanjay , Maitra Radhashree 
Published: June 2022

The ERK1/2 and PI3K pathways are the chief signaling pathways for cellular proliferation, survival, and differentiation. Overactivation of the ERK1/2 & PI3K pathways is commonly seen in cancer and is associated with poor patient prognosis. Increasing evidence is showcasing that epigenetic alterations play a major role in regulating the ERK1/2 & PI3K pathways.

Protein Arginine Methyltransferase 5 (PRMT5) is an epigenetic regulator currently undergoing clinical trials as a potential therapeutic target for cancer. PRMT5 has been shown to be overexpressed and negatively correlated with patient survival in many types of cancers. Recent studies are indicating that PRMT5 is involved in regulating the ERK1/2 & PI3K pathways. Moreover, our group's work, as well as other studies, are demonstrating that PRMT5 inhibition, as well as PRMT5 and ERK1/2 & PI3K combination therapies, show significant therapeutic effects in many types of cancers.

In this study, the Gene Expression Profiling Interactive Analysis (GEPIA) database was used to analyze the RNA-Seq data of colorectal cancer (CRC) patients from The Cancer Genome Atlas (TCGA) database. We first used the GEPIA database to determine which proteins in the ERK1/2 & PI3K pathways are expressionally correlated with PRMT5 in colon and rectum patient tumor samples. We found that the receptor proteins EGFR and FGFR3 were positively correlated with PRMT5 with a R-Value &gt; 0.61 and a P-Value &lt; 0.01. We further determined that the ERK1/2 pathway proteins KRAS, RAF, MEK, and ERK were all positively correlated with PRMT5 with a R-Value &gt; 0.73 and a P-Value &lt; 0.01. Lastly, we found that the PI3K pathway proteins PI3K, AKT, mTOR, and PTEN were positively correlated with PRMT5 with a R-Value &gt; 0.71 and a P-Value &lt; 0.01.

We next used the STRING database to analyze and determine which proteins in the ERK1/2 & PI3K pathways interact with PRMT5. We found that PRMT5 interacts with the receptor proteins EGFR and FGFR3, the ERK1/2 pathway proteins KRAS, and lastly, the PI3K pathway proteins AKT, mTOR, and PTEN with an interaction score &gt; 0.150. Finally, we then used Biorender to develop a protein network map to model the proteins in the ERK1/2 & PI3K pathways that both positively correlate with, as well as interact with, PRMT5. Our protein network map demonstrates that PRMT5 is positively correlated with (R-Value &gt; 0.61, P-Value &lt; 0.01), as well as interacts with (interaction score &gt; 0.150) the following ERK1/2 & PI3K pathway proteins: EGFR, FGFR3, KRAS, AKT, mTOR, and PTEN.

Our study thus shows further evidence that PRMT5 is positively correlated with, as well as interacts with, the ERK1/2 & PI3K pathways in CRC. These findings are significant as they make the case for additional testing of PRMT5 inhibition, as well as PRMT5 and ERK1/2 & PI3K combination therapies, for the treatment of cancer. Further analysis is currently in progress to delineate the molecular mechanisms behind PRMT5’s interactions with the ERK1/2 & PI3K pathways.

Citation Format: David Shifteh, Tzuriel Sapir, Moshe Pahmer, Sanjay Goel, Radhashree Maitra. PRMT5 is positively correlated with and interacts with the ERK1/2 & PI3K Pathways in CRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3369.