LncRNA SAMMSON Mediates Adaptive Resistance to RAF Inhibition in BRAF-Mutant Melanoma Cells
LncRNA SAMMSON Mediates Adaptive Resistance to RAF Inhibition in BRAF-Mutant Melanoma Cells
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LncRNA SAMMSON 介导 BRAF 突变黑色素瘤细胞对 RAF 抑制的适应性抵抗
DOI：
10.1158/0008-5472.can-20-3145
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发表时间：
2021-06-01
期刊：
影响因子：
11.2
通讯作者：
Liu, Jiankang
中科院分区：
文献类型：
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作者：
Han, Shujun;Yan, Yuwei;Liu, Jiankang
长链非编码RNA（lncRNA）SAMMSON是人黑色素瘤细胞生长和存活所必需的。然而，SAMMSON是否调节突变型BRAF黑色素瘤细胞对RAF抑制剂的反应仍然未知。在这项工作中，我们发现SAMMSON在抑制ERK信号传导后被快速诱导，并且SAMMSON过表达赋予黑色素瘤细胞对维罗非尼诱导的细胞毒性的抗性。SOX 10介导了维罗非尼对SAMMSON的转录诱导，而K55处的SOX 10类小泛素化对于该功能至关重要。此外，SAMMSON的耗尽激活了p53信号传导，这依赖于SAMMSON相互作用蛋白CARF。SAMMSON的耗竭使突变BRAF黑色素瘤细胞在体外和体内对RAF抑制剂敏感，而CARF敲低逆转了增强的敏感性。总之，这些研究结果表明，SAMMSON可能作为一个新的调解人的适应性耐药性RAF抑制剂在黑色素瘤通过调制CARF-p53 signaling.Significance：这项研究突出了SAMMSON/CARF/p53信号轴的作用，在调制的适应性耐药性突变BRAF黑色素瘤RAF抑制剂。
The long noncoding RNA (lncRNA) SAMMSON is required for human melanoma cell growth and survival. However, whether SAMMSON regulates the response of mutant BRAF melanoma cells to RAF inhibitors remains unknown. In this work, we showed that SAMMSON is rapidly induced upon inhibition of ERK signaling, and SAMMSON overexpression conferred resistance to vemurafenib-induced cytotoxicity in melanoma cells. SOX10 mediated transcriptional induction of SAMMSON by vemurafenib, and SOX10 sumoylation at K55 was essential for this function. In addition, depletion of SAMMSON activated p53 signaling, which is dependent on the SAMMSON-interacting protein CARF. Depletion of SAMMSON sensitized mutant BRAF melanoma cells to RAF inhibitors in vitro and in vivo, while CARF knockdown reversed the enhanced sensitivity. In summary, these findings suggest that SAMMSON may function as a new mediator of adaptive resistance to RAF inhibitors in melanoma by modulating CARF-p53 signaling.Significance: This study highlights the role of a SAMMSON/CARF/p53 signaling axis in modulating the adaptive resistance of mutant BRAF melanoma to RAF inhibitors.