SOX9 Transcriptionally Regulates mTOR-Induced Proliferation of Basal Cell Carcinomas.
SOX9 Transcriptionally Regulates mTOR-Induced Proliferation of Basal Cell Carcinomas.
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DOI：
10.1016/j.jid.2018.01.040
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发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
Bickers DR
中科院分区：
文献类型：
--
作者：
Kim AL;Back JH;Chaudhary SC;Zhu Y;Athar M;Bickers DR
目前在基底细胞痣综合征（BCNS）患者中可用的SMO靶向治疗与大量肿瘤复发和临床耐药相关。绕过SMO和/或识别Hedgehog （Hh）通路的其他下游组分的策略可以提供具有更好治疗指数的新型抗肿瘤靶点。SOX9是一种Hh/ gli调控的转录因子，已知在bcc中过表达。对sox9响应元件的序列基序搜索在mTOR的启动子区域发现了三个基序。在小鼠BCC细胞中，SOX9占据mTOR启动子并诱导其转录活性。shrna介导的SOX9的下调，以及伊曲康唑和vismodegib对SMO的抑制，降低了mTOR的表达和已知下游mTOR靶点的磷酸化。这些影响最终导致BCC细胞的增殖能力降低，证明了Hh和mTOR通路之间能够驱动BCC生长的直接机制联系。此外，雷帕霉素（一种药理mTOR抑制剂）抑制了紫外线诱导的Ptch1+/−/SKH-1小鼠BCC的生长，该模型与BCNS患者BCC加速生长模式非常相似。我们的数据表明，Hh信号通过SOX9向mTOR聚集，并强调SOX9 - mTOR轴是SMO下游可行的额外靶标，可以增强BCC患者的肿瘤消除。
Currently available SMO targeted therapies in patients with basal cell nevus syndrome (BCNS) are associated with substantial tumor recurrence and clinical resistance. Strategies bypassing SMO and/or identifying additional downstream components of the Hedgehog (Hh) pathway could provide novel anti-tumor targets with a better therapeutic index. SOX9 is a Hh/GLI-regulated transcription factor known to be overexpressed in BCCs. A sequence motif search for SOX9-responsive elements identified three motifs in the promoter region of mTOR. In murine BCC cells, SOX9 occupies the mTOR promoter and induces its transcriptional activity. shRNA-mediated knockdown of SOX9, as well as SMO inhibition by itraconazole and vismodegib, reduces mTOR expression and the phosphorylation of known downstream mTOR targets. These effects culminate in diminishing the proliferative capacity of BCC cells, demonstrating a direct mechanistic link between the Hh and mTOR pathways capable of driving BCC growth. Furthermore, rapamycin, a pharmacologic mTOR inhibitor, suppressed growth of UV-induced BCCs in Ptch1+/−/SKH-1 mice, a model that closely mimics the accelerated BCC growth pattern of patients with BCNS. Our data demonstrate that Hh signaling converges on mTOR via SOX9, and highlight the SOX9–mTOR axis as a viable additional target downstream of SMO that could enhance tumor elimination in BCC patients.
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影响因子：
4.8
作者：
Fonseca, Bruno D.;Alain, Tommy;Proud, Christopher G.
通讯作者：
Proud, Christopher G.
DOI：
10.1073/pnas.1620993114
发表时间：
2017-05-30
影响因子：
11.1
作者：
Jeselsohn, Rinath;Cornwell, MacIntosh;Brown, Myles
通讯作者：
Brown, Myles
SHH和P50/BCL3信号传导串扰驱动BCC在Gorlin综合征中的发病机理。
影响因子：
--
作者：
Chaudhary SC;Tang X;Arumugam A;Li C;Srivastava RK;Weng Z;Xu J;Zhang X;Kim AL;McKay K;Elmets CA;Kopelovich L;Bickers DR;Athar M
通讯作者：
Athar M
影响因子：
6.5
作者：
Kim, AL;Athar, M;Gautier, J
通讯作者：
Gautier, J
影响因子：
11.1
作者：
Eberl, Markus;Klingler, Stefan;Mangelberger, Doris;Loipetzberger, Andrea;Damhofer, Helene;Zoidl, Kerstin;Schnidar, Harald;Hache, Hendrik;Bauer, Hans-Christian;Solca, Flavio;Hauser-Kronberger, Cornelia;Ermilov, Alexandre N.;Verhaegen, Monique E.;Bichakjian, Christopher K.;Dlugosz, Andrzej A.;Nietfeld, Wilfried;Sibilia, Maria;Lehrach, Hans;Wierling, Christoph;Aberger, Fritz
通讯作者：
Aberger, Fritz