Research Insight - Transcription Factor JUN-mediates the Formation of R-loop in seRNA and Promotes Metastasis of Nasopharyngeal Carcinoma

Research Insight - Transcription Factor JUN-mediates the Formation of R-loop in seRNA and Promotes Metastasis of Nasopharyngeal Carcinoma

2024-02-14 15:00:46

Faqing Tang’s team from Hunan Cancer Hospital has made new progress in the molecular mechanism of nasopharyngeal carcinoma metastasis. The research results have been published in the Cell Death & Disease. (IF=9.0, Q1).

Enhancers are DNA remote elements that can activate or increase the transcription of related genes in cell type specific biological processes. Transcription factors (TF) bind to these enhancers through special recognition sequences and cooperate with cofactors to form chromatin loops between enhancers and promoters.

Super enhancers (SEs) are a series of enhancers, also known as stretching enhancers, located near genes crucial for cell survival and tumor development, promoting the carcinogenic process by activating neighboring genes. SEs connect several promoters, typically hundreds of dry bases away from their target genes.

Compared to typical enhancers (TEs), enhancers contain larger open chromatin domains characterized by high levels of H3K27 acetylation (H3K27ac) and enrichment for TEs binding. SEs typically bind to RNA polymerase II (RNAPII) to produce bidirectional non coding RNA called seRNA. The absence of seRNAs or non coding RNAs similar to seRNA can lead to downregulation of egg self coding genes associated with it, and seRNAs play an important role in tumor development.

Nasopharyngeal carcinoma (NPC) is a malignant tumor that originates from the heteropharynx and has high metastatic potential. Although nasopharyngeal carcinoma is sensitive to radiotherapy, the prognosis of patients with distant metastasis is still poor. 1,4-dinitropiperazine (DNP) is the main volatile nitrosamine in pickled foods. Some studies have shown that DNP can promote NPC carcinogenesis and metastasis in vivo.

In this study, a novel molecular mechanism for nasopharyngeal carcinoma metastasis was demonstrated.

A combination of global run on sequencing, chromatin immunoprecipitation sequencing, and RNA sequencing was used to screen for a specific seRNA (seRNA NPCM) associated with heteropharyngeal cancer metastasis, which was identified as a transcriptional regulator of N-myc downstream regulatory gene 1 (NDRG1). It has been confirmed that the main transcription factor JUN is crucial for activating the production of seRNA NPCM. The transcription of seRNA NPCM from the inter gene region can promote in vitro and in vivo metastasis of nasopharyngeal carcinoma. In nasopharyngeal carcinoma patients, the expression of seRNA NPCM indicates poor condition. SeRNA-NPCM forms RNA DNA loops (R-loops) in the SE region and binds to hnRNPR on the NDRG1 and TRIB1 promoters, thereby promoting enhancer promoter loop formation and gene transcription. SERNA-NPCM also interacts directly with ACTA1. These findings are of great significance for clarifying the molecular mechanism of seRNA-NPCM regulating the promoter in the process of nasopharyngeal tumor metastasis.

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▲ The model of seRNA-NPCM regulating NDRG1 and TRIB1 expression through R-loop formation

To confirm the effect of seRNA-NPCM on the in vivo metastasis of nasopharyngeal carcinoma, the authors used Biolight Biotechnology’s AniView series multimodal in vivo animal imaging system to capture the metastasis process of nasopharyngeal carcinoma tumors. The results showed that the expression of seRNA-NPCM significantly enhanced the metastasis of nasopharyngeal carcinoma in vivo.

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In vivo imaging of nude mice metastatic status by luciferase-based bioluminescence imaging. Yellow arrow, metastatic nodules.
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Jia, Q., Tan, Y., Li, Y. et al. JUN-induced super-enhancer RNA forms R-loop to promote nasopharyngeal carcinoma metastasis. Cell Death Dis 14, 459 (2023).