Transition In Human Cancer Research Articles

Abstract 853: C1orf116, a gene with unknown function, is a novel driver of epithelial phenotype in epithelial-to-mesenchymal transition in human cancer

Abstract Metastatic prostate cancer is an incurable lethal disease and is the cause of death for 28,000 men in the US annually. In order for a cancer cell to metastasize from the primary tumor, it must move. In a critical early event of metastasis, a rare population of cells in the primary tumor undergoes a phenotype switch from a proliferating epithelial cell to gaining the migratory capacity of a mesenchymal cell, a process, termed epithelial-to-mesenchymal transition (EMT). To identify previously overlooked regulators of EMT, we undertook a multi-study gene expression array analysis (15 published gene expression studies; 95 total samples; 6 cancer types) and identified C1orf116 as a candidate driver of the epithelial phenotype in EMT across multiple cancer types. Of note, C1orf116 is an unnamed gene of unknown function that is largely uncharacterized in any setting, including in cancer biology or in EMT. To substantiate its potential role in EMT, we queried the NCI-60 cell line collection gene expression dataset and found that C1orf116 shared a similar expression pattern with epithelial marker genes (ESRP1, ESRP2, OVOL1, OVOL2) and a converse expression pattern to mesenchymal marker genes (CDH2, SNAI2, VIM). Moreover, we found that C1orf116 expression is decreased in metastatic prostate cancer tumors compared to localized disease (Oncomine), suggesting the potential for clinical translation. To specifically interrogate the role of C1orf116 in EMT, we utilized the PC3 cell line, an in vitro model of prostate cancer EMT. We found that C1orf 116 expression was higher in an epithelial PC3 cell line (PC3-epi) compared to PC3 cells that had undergone a stable EMT (PC3-emt). Moreover, shRNA-mediated knockdown of C1orf116 expression in PC3-epi cells resulted in decreased gene expression of canonical epithelial markers (OVOL1, ESRP1, CDH1) and elevated expression of standard mesenchymal markers (CDH2, ZEB1, VIM), suggesting a role as a driver of the epithelial phenotype. Interestingly, the sole publication specifically studying C1orf116 describes it as Specifically Androgen Regulated Gene (SARG). The authors demonstrate the presence of an androgen response element upstream of the C1orf116 start site the in androgen-responsive prostate cancer cell line LNCaP. Our data indicate a role for C1orf116 in the androgen receptor-negative prostate cancer cell line PC3, suggesting a non-androgen-mediated role for C1orf116 in prostate cancer. In addition to elucidating its role in EMT, work is underway to characterize the RNA and protein products of C1orf116. Alternative splicing results in two transcripts of varying length that likely give rise to at least two protein product sizes. RNA sequencing and mass spectrometry will reveal transcript and protein identity and provide insight into potential isoform switching regulating EMT and other processes. Citation Format: Sarah R. Amend, James Hernandez, Princy Parsana, Kenneth J. Pienta. C1orf116, a gene with unknown function, is a novel driver of epithelial phenotype in epithelial-to-mesenchymal transition in human 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 853. doi:10.1158/1538-7445.AM2017-853

Epithelial–mesenchymal transition in human cancer: Comprehensive reprogramming of metabolism, epigenetics, and differentiation

The epithelial-mesenchymal transition (EMT) is a developmental process that is important for embryogenesis, wound healing, organ fibrosis, and cancer metastasis. Cancer-associated EMT is not a simple process to acquire migration and invasion ability, but a complicated and comprehensive reprogramming, involved in metabolism, epigenetics and differentiation, through which differentiated epithelial cancer cells reverse to an undifferentiated state, not only expressing stem cell markers, but also acquiring stem cell-like functions. Here we review recent ideas and discoveries that illustrate the links among metabolism, epigenetics, and dedifferentiation during EMT, with special emphasis on the primary driving force and ultimate goal of cancer-associated EMT - of the energy and for the energy. Furthermore, we highlight on the specificity of epigenetic modification during EMT, with an aim to explain how the repression of epithelial genes and activation of mesenchymal genes are coordinated simultaneously through EMT. Finally, we provide an outlook on anti-EMT therapeutic approach on epigenetic and metabolic levels, and discuss its potential for clinical application.

Transcription Factors OVOL1 and OVOL2 Induce the Mesenchymal to Epithelial Transition in Human Cancer

Cell plasticity regulated by the balance between the mesenchymal to epithelial transition (MET) and the opposite program, EMT, is critical in the metastatic cascade. Several transcription factors (TFs) are known to regulate EMT, though the mechanisms of MET remain unclear. We demonstrate a novel function of two TFs, OVOL1 and OVOL2, as critical inducers of MET in human cancers. Our findings indicate that the OVOL-TFs control MET through a regulatory feedback loop with EMT-inducing TF ZEB1, and the regulation of mRNA splicing by inducing Epithelial Splicing Regulatory Protein 1 (ESRP1). Using mouse prostate tumor models we show that expression of OVOL-TFs in mesenchymal prostate cancer cells attenuates their metastatic potential. The role of OVOL-TFs as inducers of MET is further supported by expression analyses in 917 cancer cell lines, suggesting their role as crucial regulators of epithelial-mesenchymal cell plasticity in cancer.