Prostate Cancer (CaP) is the most common non-cutaneous form of cancer in men and is the second leading cause of cancer mortality in men in the USA. In human CaP, gene fusion between androgen responsive regulatory elements at the 5' untranslated region of TMPRSS2 and ETS-related genes (ERG) is present in at least 50% of the prostate tumors. To identify and investigate the underlying mechanisms of ERG-associated CaP, we developed ERG-inducible LNCaP cell system. In this present study, we investigated the unique cellular transcriptome associated with over-expressed ERG in CaP cells. Our data from comprehensive transcriptome analyses, illustrate a distinct signature that distinguishes ERG-dependent and ERG-independent CaP. The data highlight the significant heterogeneity among the transcript. Out of the 527 differentially expressed genes, 232 genes were up-regulated and 295 genes were down-regulated in response to ERG. Subsequent, in silico analyses indicate that these differentially expressed genes were associated with many pathways and functions. The most significantly differentially expressed genes were associated with cell cycle regulation. The top-ranked biological functions affected by ERG over-expression include Cell Cycle (p < 1.42E-04), Cellular Growth and Proliferation (p < 1.23E-04), Cellular Development (p <1.23E-04), Cell Death and Survival (p < 1.37E-04), and Cellular Assembly and Organization (p < 1.42E-04). Further analyses indicate a strong association with known cancer networks. The top-ranked canonical pathways enriched in ERG-positive compared to ERG-negative LNCaP cells include, Cell Cycle Control of Chromosomal Replication (p=2.69E-16), Role of CHK Proteins in Cell Cycle Checkpoint Control (p=3.16E-11), Cell Cycle: G2/M DNA Damage Checkpoint Regulation (p=1.34E-09), Role of BRCA1 in DNA Damage Response (p=4.05E-08) and Estrogen-mediated S-phase Entry (p =5.51E-08). These findings indicate new insights into the complexity of TMPRESS2-ERG gene fusion, and may help understand mechanistic pathways which promote growth and progression of CaP.
Citation Format: Parameet Kumar, Joyeeta Chakraborty, Raghunath Chatterjee, Gauthaman Sukumar, Clifton L. Dalgard, Kevin Babcock, Albert Dobi, Taduru L. Sreenath, Roopa Biswas. Comparative RNA-seq analysis reveals dys-regulation of major canonical pathways in ERG-inducible LNCaP cell progression model of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3569. doi:10.1158/1538-7445.AM2017-3569