PDF(Pubmed)
Abstract：
Nasopharyngeal carcinoma (NPC), primarily found in the southern region of China, is a malignant tumor known for its highly metastatic characteristics. The high mortality rates caused by the distant metastasis and disease recurrence remain unsolved clinical problems. In clinic, the berberine (BBR) compound has widely been in NPC therapy to decrease metastasis and disease recurrence, and BBR was documented as a main component with multiple anti-NPC effects. However, the mechanism by which BBR inhibits the growth and metastasis of nasopharyngeal carcinoma remains elusive. Herein, we show that BBR effectively inhibits the growth, metastasis, and invasion of NPC via inducing a specific super enhancer (SE). From a mechanistic perspective, the RNA sequencing (RNA-seq) results suggest that the RAS-RAF1-MEK1/2-ERK1/2 signaling pathway, activated by the epidermal growth factor receptor (EGFR), plays a significant role in BBR-induced autophagy in NPC. Blockading of autophagy markedly attenuated the effect of BBR-mediated NPC cell growth and metastasis inhibition. Notably, BBR increased the expression of EGFR by transcription, and knockout of EGFR significantly inhibited BBR-induced microtubule associated protein 1 light chain 3 (LC3)-II increase and p62 inhibition, proposing that EGFR plays a pivotal role in BBR-induced autophagy in NPC. Chromatin immunoprecipitation sequencing (ChIP-seq) results found that a specific SE existed only in NPC cells treated with BBR. This SE knockdown markedly repressed the expression of EGFR and phosphorylated EGFR (EGFR-p) and reversed the inhibition of BBR on NPC proliferation, metastasis, and invasion. Furthermore, BBR-specific SE may trigger autophagy by enhancing EGFR gene transcription, thereby upregulating the RAS-RAF1-MEK1/2-ERK1/2 signaling pathway. In addition, in vivo BBR effectively inhibited NPC cells growth and metastasis, following an increase LC3 and EGFR and a decrease p62. Collectively, this study identifies a novel BBR-special SE and established a new epigenetic paradigm, by which BBR regulates autophagy, inhibits proliferation, metastasis, and invasion. It provides a rationale for BBR application as the treatment regime in NPC therapy in future.
摘要：
鼻咽癌(NPC),主要发现于中国南部地区,是一种以高度转移特性而闻名的恶性肿瘤。由远处转移和疾病复发引起的高死亡率仍然是临床上尚未解决的问题。在临床上,黄连素（BBR）化合物已广泛用于鼻咽癌治疗，以减少转移和疾病复发，并且BBR被记录为具有多种抗NPC作用的主要成分。然而,BBR抑制鼻咽癌生长和转移的机制尚不清楚。在这里，我们表明，BBR有效地抑制了生长，转移,并通过诱导特异性超级增强子（SE）入侵NPC。从机械的角度来看，RNA测序(RNA-seq)结果表明RAS-RAF1-MEK1/2-ERK1/2信号通路,由表皮生长因子受体（EGFR）激活，在BBR诱导的NPC自噬中起重要作用。自噬的阻断显著减弱了BBR介导的NPC细胞生长和转移抑制的作用。值得注意的是,BBR通过转录增加EGFR的表达，和敲除EGFR显著抑制BBR诱导的微管相关蛋白1轻链3(LC3)-II的增加和p62抑制,提示EGFR在BBR诱导的NPC自噬中起关键作用。染色质免疫沉淀测序（ChIP-seq）结果发现，仅在BBR处理的NPC细胞中存在特异性SE。这种SE敲除明显抑制了EGFR和磷酸化EGFR（EGFR-p）的表达，并逆转了BBR对NPC增殖的抑制作用。转移,和入侵。此外，BBR特异性SE可能通过增强EGFR基因转录触发自噬，从而上调RAS-RAF1-MEK1/2-ERK1/2信号通路。此外,体内BBR有效抑制NPC细胞生长和转移，随着LC3和EGFR的增加和p62的减少。总的来说，这项研究确定了一种新的BBR-特殊SE，并建立了一种新的表观遗传范式，BBR调节自噬，抑制增殖，转移,和入侵。它为BBR作为未来NPC治疗中的治疗方案的应用提供了理论基础。
