Super-Enhancer Induced IL-20RA Promotes Proliferation/Metastasis and Immune Evasion in Colorectal Cancer

Abstract

Unveiling key oncogenic events in malignancies is the key to improving the prognosis and therapeutic outcome of malignancies. Lines of evidence have shown that super-enhancers control the expression of genes that determine the cell fate, but the oncogenic super-enhancers in colorectal cancer (CRC) and their impact on carcinogens remain largely unexplored. Here, we identified a new oncogenic super-enhancer-regulated gene, IL-20RA, in CRC. Using the integrative analysis of H3K27ac ChIP-seq and RNA-seq in CRC tumors and normal colon tissues, we obtained a series of oncogenic super-enhancers in CRC. We found that super-enhancer inhibition by JQ-1 or iBET-151 suppressed the growth of tumor cells and inhibited the expression of IL-20RA. We found that IL-20RA was highly expressed in the tumor tissue of CRC and related to the advanced stage. Further functional studies showed that knockdown of IL-20RA inhibited the growth and metastasis of CRC. In addition, we found that IL-20RA was involved in regulating oncogenic and immune pathways and affecting the expression of genes related to cell proliferation and immune evasion in CRC. Together, our study demonstrated a novel oncogene in CRC and shed new light on oncogenic super-enhancer contributions to cell proliferation and immune escape.

Inflammatory Immune-Associated eRNA: Mechanisms, Functions and Therapeutic Prospects

“…The inflammatory immune role of eRNA in tumors was first reported by Chen et al ( 99 ), demonstrating that H. pylori stimulate bromodomain-containing factor Brd4 recruitment to the BIRC3 enhancer, which promotes BIRC3 eRNA synthesis and cIAP2 expression, which inhibits caspase-3 activation and enhances apoptosis resistance in gastric epithelial cells. Additionally, some studies have suggested the presence of oncogenic SEs in colorectal cancer and confirmed their involvement in regulating oncogenic and immune pathways in colorectal cancer by modulating IL-20RA expression, affecting cell proliferation and immune evasion-related gene ecpression ( 162 ). Pancreatitis accelerates Kras mutation-driven tumorigenesis in mice, which is mostly found in pancreatic ductal adenocarcinoma ( 163 ).…”

“…Additionally, a decrease in MYC mRNA was found on the knockdown of the corresponding eRNA ( 158 ). JQ1 was demonstrated to decrease the transcriptionally activated eRNAs of SEs, causing the down-regulation of IL-20RA expression and inhibition of growth, metastasis and immune escape in colorectal cancer ( 162 ). Therefore, JQ1 regulates enhancer transcription and eRNA synthesis by affecting the mediator complex, which regulates the downstream target genes to modulate the disease process.…”

Superenhancers as master gene regulators and novel therapeutic targets in brain tumors

“…SEs were initially discovered in embryonic stem cells (ESCs), with ESC-specific master transcription factors Oct4, Sox2, and Nanog binding to enhancer elements and recruiting mediators to activate the gene transcription program 12 . Subsequently, SEs were identified in other cells, including cancer cells 13,14 . As novel epigenetic regulatory elements, SEs precisely regulate oncogene transcriptional activation during tumorigenesis and may be potential therapeutic targets 15,16 .…”

The Emerging Role of Super-enhancers as Therapeutic Targets in The Digestive System Tumors

“…However, only a subset of patients responed to immunotherapy whereas others show minimal or no response because of variations in the complex tumor immune microenvironment [24]. The immune response of digestive system tumors is also regulated by SEs [25]. A Recent study showed that SEs promote chemoresistance of tumors by aberrant transcription of genes involved in chemoresistance [26].…”

“…In breast cancer, CD47 expression is upregulated by a CD47-associated SE [72]. The upregulation of SE-regulated IL-20RA is associated with increased immune evasion of CRC cells through oncogenic and immune response pathways that reduce infiltration of N1 neutrophils, M1 macrophages, and T cells [25].…”