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Mol Cell：OTUB2独立于Hippo-信号直接激活YAP/TAZ并促进肿瘤转移的机制

2018-12-08 佚名 浙江大学生命科学研究院

OTUB2肿瘤转移
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近期，浙江大学生命科学研究院张龙实验室在Molecular Cell发表题为“OTUB2 promotes cancer metastasis via Hippo-independent activation of YAP and TAZ”的研究论文，揭示了去泛素化酶OTUB2不依赖于Hippo信号直接激活YAP/TAZ的分子机制，解释了恶性肿瘤中YAP/TAZ蛋白高度积累的原因。

近期，浙江大学生命科学研究院张龙实验室在Molecular Cell发表题为“OTUB2 promotes cancer metastasis via Hippo-independent activation of YAP and TAZ”的研究论文，揭示了去泛素化酶OTUB2不依赖于Hippo信号直接激活YAP/TAZ的分子机制，解释了恶性肿瘤中YAP/TAZ蛋白高度积累的原因。

转录调节因子 YAP/TAZ在肿瘤的转移和恶化中有着重要的作用。在恶性肿瘤中YAP/TAZ显示出很强的激活，YAP/TAZ的激活可以诱导肿瘤干细胞特性的产生，促进肿瘤的生存和转移，增强耐药性，但在乳腺癌的临床病人样本中，并没有发现类似肝癌和髓母细胞瘤中YAP基因的扩增，TAZ基因的扩增也相对很少。相反，Hippo-信号的组分在上述肿瘤中很少发生突变，那么是什么原因导致恶性肿瘤YAP/TAZ的高表达和激活呢？

该项研究中，张龙研究团队在乳腺癌转移过程中发现OTUB2是一个潜在的促进乳腺癌转移的因素。实验证明OTUB2主要通过促进乳腺癌干细胞的产生来增强肿瘤的转移。OTUB2高表达的乳腺癌病人倾向于较差的生存预期；基因富集分析发现，OTUB2与抑癌基因p53/PTEN/BRCA等失活和原癌基因KRAS的激活等特征相关。为了探究OTUB2促进癌症转移的分子机制，研究人员综合利用RNA-seq转录组和串联质谱蛋白组等方法证实OTUB2激活YAP/TAZ信号通路；OTUB2可以去除YAP/TAZ的多聚泛素化链从而稳定YAP/TAZ且OTUB2对YAP/TAZ的稳定作用不依赖于上游Hippo的失活。非常有意思的是，从原核细胞中纯化的OTUB2并不能在体外直接去除OTUB2的泛素化；免疫共沉淀与YAP/TAZ相互作用的去泛素化酶时也并未发现很强的结合蛋白；这这些结果提示OTUB2对YAP/TAZ的调控活性可能受到其本身蛋白翻译后修饰的调控或触发。

进一步研究发现，OTUB2的赖氨酸233位会被多聚SUMO化修饰且SUMO化修饰对于OTUB2调控 YAP/TAZ是必需的。当SUMO化位点发生失活性突变后，OTUB2既不能与YAP/TAZ发生相互作用，也不能去除YAP /TAZ的泛素化。相反，模拟SUMO化修饰的OTUB2则显示出更强的针对YAP/TAZ的去泛素化能力。SUMO化修饰经常通过 SUMO：SIM相互作用进一步调控底物蛋白的功能。该研究发现，YAP和TAZ上都存在进化上（从果蝇到人）高度保守的SIM基序，介导了YAP/TAZ与多聚SUMO化的OTUB2相互结合。在一系列促肿瘤转移的因子中，研究人员发现EGF会增强OTUB2的SUMO化并进一步发现其其下游KRAS的激活可以强烈地促进OTUB2的SUMO化从而稳定YAP/TAZ的蛋白水平。尽管KRAS、HRAS和N-RAS的突变在乳腺癌中相对罕见，但RAS信号通路的在50%的乳腺癌中高度活化，被认为是肿瘤复发的主要原因。因此，该研究不仅揭示了去泛素化酶 OTUB2激活YAP/TAZ、逃脱Hippo控制并促进癌症转移的分子机制，也首次将YAP/TAZ激活的信号网络纳入为EGF/RAS的下游。EGF受体信号传导中的激活突变经常在人类癌症中发现，突变体EGFR作为癌症治疗的有效靶标。基于该项研究，RAS或EGFR产生的致癌信号可能部分经由YAP / TAZ活化介导。此外，靶向YAP / TAZ可能是RAS突变或RAS激活的肿瘤的潜在治疗策略。


图注：OTUB2调控YAP/TAZ活性促进肿瘤恶化和转移的工作示意图

该项研究得到中国科技部重点研发计划（2016YFA0502500 to L.Z.）、国家自然科学基金（31471315， 31671457， 31741086 and 91753139 to L.Z.）、浙江省杰出青年基金（LR14C070001 to L.Z.）、浙江省科技重大项目（No. 2015C03045 to M.Z.）等基金的支持。

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    2019-07-03 gujh

    #YAP#

    0

  2. [GetPortalCommentsPageByObjectIdResponse(id=2081908, encodeId=8059208190876, content=<a href='/topic/show?id=c2971893397' target=_blank style='color:#2F92EE;'>#YAP#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=18933, encryptionId=c2971893397, topicName=YAP)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=3333505, createdName=gujh, createdTime=Wed Jul 03 11:59:00 CST 2019, time=2019-07-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1961296, encodeId=f76519612961e, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Mon Oct 14 07:59:00 CST 2019, time=2019-10-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1714808, encodeId=fccd1e14808df, content=<a href='/topic/show?id=021230e312' target=_blank style='color:#2F92EE;'>#AZ#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=3073, encryptionId=021230e312, topicName=AZ)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=9e5031899089, createdName=12498e5fm22(暂无昵称), createdTime=Mon May 20 20:59:00 CST 2019, time=2019-05-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1871021, encodeId=49ab18e102155, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Tue Feb 05 05:59:00 CST 2019, time=2019-02-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1291644, encodeId=ef5b129164475, content=<a href='/topic/show?id=137a831151a' target=_blank style='color:#2F92EE;'>#肿瘤转移#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=46, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83115, encryptionId=137a831151a, topicName=肿瘤转移)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1be8234, createdName=sunyl07, createdTime=Mon Dec 10 02:59:00 CST 2018, time=2018-12-10, status=1, ipAttribution=)]
    2019-10-14 维他命

    #CEL#

    0

  3. [GetPortalCommentsPageByObjectIdResponse(id=2081908, encodeId=8059208190876, content=<a href='/topic/show?id=c2971893397' target=_blank style='color:#2F92EE;'>#YAP#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=18933, encryptionId=c2971893397, topicName=YAP)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=3333505, createdName=gujh, createdTime=Wed Jul 03 11:59:00 CST 2019, time=2019-07-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1961296, encodeId=f76519612961e, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Mon Oct 14 07:59:00 CST 2019, time=2019-10-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1714808, encodeId=fccd1e14808df, content=<a href='/topic/show?id=021230e312' target=_blank style='color:#2F92EE;'>#AZ#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=3073, encryptionId=021230e312, topicName=AZ)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=9e5031899089, createdName=12498e5fm22(暂无昵称), createdTime=Mon May 20 20:59:00 CST 2019, time=2019-05-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1871021, encodeId=49ab18e102155, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Tue Feb 05 05:59:00 CST 2019, time=2019-02-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1291644, encodeId=ef5b129164475, content=<a href='/topic/show?id=137a831151a' target=_blank style='color:#2F92EE;'>#肿瘤转移#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=46, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83115, encryptionId=137a831151a, topicName=肿瘤转移)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1be8234, createdName=sunyl07, createdTime=Mon Dec 10 02:59:00 CST 2018, time=2018-12-10, status=1, ipAttribution=)]
    2019-05-20 12498e5fm22(暂无昵称)

    #AZ#

    0

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    2019-02-05 zhaozhouchifen

    #Cell#

    0

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    2018-12-10 sunyl07

    #肿瘤转移#

    0