CANCER RESEARCH | REVIEW Implications of Enhancer Transcription and eRNAs in Cancer Santanu Adhikary 1,2 , Siddhartha Roy 2 , Jessica Chacon 3 , Shrikanth S. Gadad 3,4,5,6 , and Chandrima Das 1,7 ABSTRACT ◥ Despite extensive progress in developing anticancer therapies, therapy resistance remains a major challenge that promotes disease relapse. The changes that lead to therapy resistance can be intrinsically present or may be initiated during treatment. Genetic and epigenetic heterogeneity in tumors make it more challenging to deal with therapy resistance. Recent advances in genome-wide analyses have revealed that the deregulation of distal gene regulatory elements, such as enhancers, appears in several pathophysiological conditions, including cancer. Beyond the conventional function of enhancers in recruiting transcrip- tion factors to gene promoters, enhancer elements are also transcribed into noncoding RNAs known as enhancer RNAs (eRNA). Accumulating evidence suggests that uncontrolled enhancer activity with aberrant eRNA expression promotes oncogenesis. Interestingly, tissue-specific, transcribed eRNAs from active enhancers can serve as potential therapeutic targets or biomarkers in several cancer types. This review provides a comprehensive overview of the mechanisms of enhancer tran- scription and eRNAs as well as their potential roles in cancer and drug resistance. Introduction Cancer is one of the leading causes of death worldwide; it is a heterogeneous disease controlled by genetic and epigenetic alterations and deregulated transcription (1, 2). Advances in DNA-based tech- nologies have led to the development of precision-based therapeutic strategies, including surgery, targeted therapy, radiation therapy, chemotherapy, hormonal therapy, and immunotherapy (3–5). Yet, most cancers evolve and become refractory to therapy, resulting in death because the continuous selection of fit cells leads to resistance against therapeutic strategies (6–8). In the past two decades, with the completion of the Human Genome Project and advances in high throughput sequencing, it has become quite feasible to identify regulatory and functional elements and determine their function, especially abnormal biological processes such as cancer. Sequencing has provided a blueprint for gene expres- sion and has led to new study areas comprising the assessment of multiple action mechanisms involved in gene regulation, providing researchers with therapeutic and diagnostic targets for many heritable diseases. Transcription is a critical regulatory step controlled by promoters, which are nearby cis-regulatory elements, and other distal regulatory elements, such as enhancers and silencing elements (9). Understanding the intricate details of transcriptional regulation at enhancers in cancer is the key to developing next-generation thera- peutic strategies to treat this ever-evolving disease. Enhancers and enhancer transcription Enhancers are short clusters of regulatory DNA elements, spanning 500–2,000 bp, that are transcribed and contain transcription factor (TF) recognition sequences. They are present either near to or distant from the target gene promoters and regulate expression across space and time (10–12). The first enhancer was described as a distal cis- regulatory DNA element of the gene activation of the simian virus 40 (SV40; ref. 13). Active enhancers have been found in undifferentiated and pluripotent embryonic stem cells, which drive gene expression to maintain pluripotency (14). However, those involved in lineage com- mitment remain inactive (15). During cellular differentiation, enhan- cers become active and control lineage specification (14, 15). Emerging studies have shown that most oncogenes are governed by actively transcribing enhancers and/or clusters of enhancers (sometimes termed super-enhancers), previously known as locus control regions (16–18). The binding of TFs to enhancers leads to the recruitment of chromatin-modifying machinery and chromatin remo- deling complexes. Enhancers are typically marked by histone mod- ifications, such as histone H3 lysine 27 acetylation (H3K27ac) and H3 lysine 4 monomethylation (H3K4me1; Fig. 1A), which result in enhancer transcription to generate enhancer RNAs (eRNA) via RNA polymerase II (RNA Pol II; Fig. 1A; refs. 19–25). The discovery of eRNAs has revealed an untapped wealth of biological information. We have just begun to understand their potential in designing strategies to combat many diseases, including cancer. eRNAs were first identified in neurons and macrophages (26, 27). eRNAs are bidirectionally transcribed from enhancers (24, 26) via RNA Pol II and are usually noncoding (10, 22, 26, 28–32). In contrast to mRNAs, the majority of these eRNAs are unspliced and have nonpolyadenylated tails (11). Furthermore, eRNAs are more unstable, more abundant, and shorter, and they are retained in the nucleus, making them vulnerable to exosome-mediated decay (11, 33–35). The lack of polyadenylation (polyA) is one of the primary causes of their 1 Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India. 2 Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India. 3 Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, Texas. 4 Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, Texas. 5 Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, Texas. 6 Cecil H. and Ida Green Center for Reproductive Biology Sciences, Department of Obstetrics and Gynaecology, University of Texas Southwestern Medical Center, Dallas, Texas. 7 Homi Bhaba National Institute, Mumbai, Maharashtra, India. Corresponding Authors: Shrikanth S. Gadad, Texas Tech University Health Sciences Center El Paso, 5001 El Paso Drive, El Paso, Texas 79905. Phone: 915-215-6431; Fax: 915-783-5222; E-mail: shrkanth.gadad@ttuhsc.edu; and Chandrima Das, Saha Institute of Nuclear Physics, Sector-I, AF Block, Bidhan Nagar, Bidhannagar, Kolkata, West Bengal 700064, India. Phone: 332-337-0221, ext. 4623; Fax: 332-337-4637; E-mail: chandrima.das@saha.ac.in Cancer Res 2021;81:4174–82 doi: 10.1158/0008-5472.CAN-20-4010 Ó2021 American Association for Cancer Research AACRJournals.org | 4174 Downloaded from http://aacrjournals.org/cancerres/article-pdf/81/16/4174/3091523/4174.pdf by guest on 08 April 2024