Phosphorylated RB Promotes Cancer Immunity by Inhibiting NF-κB Activation and PD-L1 Expression.
Phosphorylated RB Promotes Cancer Immunity by Inhibiting NF-κB Activation and PD-L1 Expression.
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磷酸化 RB 通过抑制 NF-κ B 激活和 PD-L1 表达来促进癌症免疫
DOI：
10.1016/j.molcel.2018.10.034
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发表时间：
2019-01-03
期刊：
影响因子：
16
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Jin X;Ding D;Yan Y;Li H;Wang B;Ma L;Ye Z;Ma T;Wu Q;Rodrigues DN;Kohli M;Jimenez R;Wang L;Goodrich DW;de Bono J;Dong H;Wu H;Zhu R;Huang H
肿瘤细胞中程序性死亡配体-1（PD-L1）的异常表达通过抑制癌症免疫促进癌症进展。视网膜母细胞瘤蛋白RB是已知调节细胞周期、DNA损伤反应和分化的肿瘤抑制因子。在这里，我们证明RB与核因子κB（NF-κB）蛋白p65相互作用，并且它们的相互作用主要依赖于CDK 4/6介导的RB的丝氨酸-249/苏氨酸-252（S249/T252）磷酸化。RNA-seq分析显示，RB敲低或CDK 4/6抑制剂可选择性上调包括PD-L1在内的NF-κB通路基因亚组。患者样本中S249/T252磷酸化RB与PD-L1表达呈负相关。RB衍生的S249/T252磷酸化模拟肽的表达抑制放射疗法诱导的PD-L1上调并增强放射的体内治疗功效。我们的研究结果揭示了以前未被认识到的过度磷酸化RB在抑制NF-κB活性和PD-L1表达方面的肿瘤抑制功能，并表明RB-NF-κB轴可用于克服常规或靶向治疗引发的癌症免疫逃避。已知RB通过抑制E2 F转录因子而充当肿瘤抑制因子，并且由于其被CDK磷酸化，该功能被消除。Jin et al.鉴定了CDK 4/6-磷酸化RB在通过抑制NF-κB转录活性和PD-L1表达促进癌症免疫中的先前未表征的肿瘤抑制作用。
Aberrant expression of programmed death ligand-1 (PD-L1) in tumor cells promotes cancer progression by suppressing cancer immunity. The retinoblastoma protein RB is a tumor suppressor known to regulate the cell cycle, DNA damage response, and differentiation. Here, we demonstrate that RB interacts with nuclear factor κB (NF-κB) protein p65 and that their interaction is primarily dependent on CDK4/6-mediated serine-249/threonine-252 (S249/T252) phosphorylation of RB. RNA-seq analysis shows a subset of NF-κB pathway genes including PD-L1 are selectively upregulated by RB knockdown or CDK4/6 inhibitor. S249/T252-phosphorylated RB inversely correlates with PD-L1 expression in patient samples. Expression of a RB-derived S249/T252 phosphorylation-mimetic peptide suppresses radiotherapy-induced upregulation of PD-L1 and augments therapeutic efficacy of radiation in vivo. Our findings reveal a previously unrecognized tumor suppressor function of hyperphosphorylated RB in suppressing NF-κB activity and PD-L1 expression and suggest that the RB-NF-κB axis can be exploited to overcome cancer immune evasion triggered by conventional or targeted therapies. RB is known to act as a tumor suppressor by inhibiting E2F transcription factors, and this function is abolished due to its phosphorylation by CDKs. Jin et al. identify a previously uncharacterized tumor suppressor role of CDK4/6-phosphorylated RB in promoting cancer immunity via inhibition of NF-κB transcriptional activity and PD-L1 expression.
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影响因子：
64.8
作者：
Manguso RT;Pope HW;Zimmer MD;Brown FD;Yates KB;Miller BC;Collins NB;Bi K;LaFleur MW;Juneja VR;Weiss SA;Lo J;Fisher DE;Miao D;Van Allen E;Root DE;Sharpe AH;Doench JG;Haining WN
通讯作者：
Haining WN
影响因子：
4
作者：
Inoue K;Shinohara H;Behar M;Yumoto N;Tanaka G;Hoffmann A;Aihara K;Okada-Hatakeyama M
通讯作者：
Okada-Hatakeyama M
影响因子：
82.9
作者：
Craft, N;Shostak, Y;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
50.3
作者：
Lim SO;Li CW;Xia W;Cha JH;Chan LC;Wu Y;Chang SS;Lin WC;Hsu JM;Hsu YH;Kim T;Chang WC;Hsu JL;Yamaguchi H;Ding Q;Wang Y;Yang Y;Chen CH;Sahin AA;Yu D;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
影响因子：
7.7
作者：
Narasimha AM;Kaulich M;Shapiro GS;Choi YJ;Sicinski P;Dowdy SF
通讯作者：
Dowdy SF