Carcinogen-induced super-enhancer RNA promotes nasopharyngeal carcinoma metastasis through NPM1/c-Myc/NDRG1 axis.

Chemical carcinogen is one etiology of nasopharyngeal carcinoma (NPC) occurrence, N,N'-Dinitrosopiperazine (DNP) has been verified to cause NPC cell metastasis and generate induced pluripotent stem cells (iPSCs). To investigate the oncogenic mechanism of DNP, NPC cells were exposed to DNP, and subjected to RNA-seq, GRO-seq, ChIP-seq, and data analysis. The results showed that the super-enhancer RNA (seRNA) participates in DNP-mediated NPC metastasis through regulating N-myc downstream regulated gene 1 (NDRG1). Mechanistically, DNP exposure upregulates the levels of NPC metastatic seRNA (seRNA-NPCm), seRNA-NPCm interacted with a special super-enhancer (SE) upstream of NDRG1 gene and bound to nucleophosmin (NPM1)/c-Myc complex at the NDRG1 promoter, resulting in an increase of NDRG1 transcription. Functional studies showed that DNP significantly increased the metastatic capability of NPC cells in vitro and in vivo. Knockdown of seRNA-NPCm in NPC cells impaired the capability of metastasis. Furthermore, stably overexpressing seRNA-NPCm significantly increased the metastatic ability of NPC cells, while restoration of NDRG1 levels in these cells restored their metastatic capacity. Finally, the immunohistochemistry and in situ hybridization analyses revealed that the expression of seRNA-NPCm in NPC patients is positively correlated with NDRG1, and the NDRG1 level independently predicts poor prognosis of NPC patients. Collectively, DNP induces seRNA-NPCm, and seRNA-NPCm promotes NPC metastasis through NPM1/c-Myc/NDRG1 axis.