Targeting the p300/NONO axis sensitizes melanoma cells to BRAF inhibitors.
Targeting the p300/NONO axis sensitizes melanoma cells to BRAF inhibitors.
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靶向 p300/NONO 轴使黑色素瘤细胞对 BRAF 抑制剂敏感。
DOI：
10.1038/s41388-021-01834-1
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发表时间：
2021
期刊：
影响因子：
8
通讯作者：
Lv Xiao-Bin
中科院分区：
文献类型：
--
作者：
Zhang Feifei;Tang Xiaofeng;Fan Song;Liu Xia;Sun Jun;Ju Cheng;Liang Yiping;Liu Renfeng;Zhou Ruihao;Yu Bo;Zhang Changhua;Zhang Zhiping;Kang Tiebang;Huang Guofu;Lv Xiao-Bin
靶向BRAF V600 E激酶的BRAF抑制剂（BRAFi），在50%的黑色素瘤中发现的驱动突变，显示出显着的抗肿瘤反应，但获得性耐药的常见出现仍然是一个挑战。RAF异构体CRAF和ARAF的异常表达使pERK 1/2重新激活，pERK 1/2在黑色素瘤细胞获得抗性中起关键作用。然而，RAF亚型在耐药黑色素瘤细胞中的失调机制仍然未知。在这里，我们确定了NONO与黑色素瘤细胞中的CRAF和ARAF相互作用并使其稳定，并且NONO在198 K被p300乙酰转移酶乙酰化，这通过拮抗RNF 8介导的其泛素化/降解来稳定NONO。p300和NONO的上调促进了pERK 1/2的反弹和随后的黑色素瘤细胞对BRAFi的抗性，并且ERK 1/2的激活反过来诱导p300在抗性黑色素瘤细胞中形成正反馈环。耐药黑色素瘤细胞和临床标本中p300和NONO的表达呈正相关，p300抑制剂C646在体内外均能克服耐药黑色素瘤细胞对BRAF抑制剂的耐药性。我们的研究结果表明，靶向p300-NONO-CRAF/ARAF-pERK 1/2的正反馈环可能是克服黑色素瘤患者BRAF抑制剂耐药性的极好策略。
BRAF inhibitors (BRAFi) that target BRAF V600E kinase, a driver mutation found in 50% of melanomas, show a significant antitumor response, but the common emergence of acquired resistance remains a challenge. Abnormal expression of RAF isoforms CRAF and ARAF reactivates pERK1/2, which plays crucial roles in the acquisition of resistance of melanoma cells. However, the mechanisms of dysregulation of RAF isoforms in resistant melanoma cells remain unknown. Here, we identified NONO interacted with and stabilized both CRAF and ARAF in melanoma cells, and that NONO was acetylated at 198K by p300 acetyltransferase, which stabilized NONO via antagonizing its ubiquitination/degradation mediated by RNF8. The upregulation of both p300 and NONO promoted the rebound of pERK1/2 and the subsequent resistance of melanoma cells to BRAFi, and the activation of ERK1/2 in turn induced p300 to form a positive feedback loop in resistant melanoma cells. There was a positive correlation between p300 and NONO in resistant melanoma cells and clinical samples, and p300 inhibitor C646 overcame the resistance of resistant melanoma cells to BRAF inhibitors in vitro and in vivo. Our findings reveal that targeting the positive feedback loop of p300-NONO-CRAF/ARAF-pERK1/2 may be excellent strategies to overcome the resistance of BRAF inhibitors for melanoma patients.