The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma
The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma
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DOI：
10.1016/j.jid.2019.09.024
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发表时间：
2020-06-01
影响因子：
6.5
通讯作者：
Saville, Mark K.
中科院分区：
文献类型：
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作者：
McHugh, Angela;Fernandes, Kenneth;Saville, Mark K.
我们进行了一个小的干扰RNA筛选，以确定皮肤鳞状细胞癌（cSCC）治疗的泛素/泛素样系统的目标。我们提供了E3泛素连接酶MARCH 4、ATP酶p97/VCP、去泛素化酶USP 8、cullin-RING连接酶（CRL）4底物受体CDT 2/DTL和后期促进复合物/环体（APC/C）组分敲低的选择性抗cSCC活性的证据。通过CDT 2敲低特异性地减弱CRL 4（CDT 2）在杀死cSCC细胞方面可能比通常通过RBX 1或DDB 1消耗靶向CRL或CRL 4更有效。通过靶向其阻遏物EMI 1来抑制APC/C或强制APC/C活化都是潜在的治疗方法。我们观察到cSCC细胞可被USP 8（DUBs-IN-3/化合物22 c）和NEDD 8 E1活化酶/CRL（MLN 4924/pevonedistat）的小分子抑制剂选择性杀死。相当大比例的cSCC细胞系对MLN 4924高度敏感。对蛋白质稳态缺陷作出反应的途径涉及p97抑制的抗cSCC活性。靶向USP 8可以减少参与cSCC发展的生长因子受体的表达。EMI 1和CDT 2缺失可选择性地引起cSCC细胞中的DNA再复制和DNA损伤。
We performed a small interfering RNA screen to identify targets for cutaneous squamous cell carcinoma (cSCC) therapy in the ubiquitin/ubiquitin-like system. We provide evidence for selective anti-cSCC activity of knockdown of the E3 ubiquitin ligase MARCH4, the ATPase p97/VCP, the deubiquitinating enzyme USP8, the cullin-RING ligase (CRL) 4 substrate receptor CDT2/DTL, and components of the anaphase-promoting complex/cyclosome (APC/C). Specifically attenuating CRL4(CDT2) by CDT2 knockdown can be more potent in killing cSCC cells than targeting CRLs or CRL4s in general by RBX1 or DDB1 depletion. Suppression of the APC/C or forced APC/C activation by targeting its repressor EMI1 are both potential therapeutic approaches. We observed that cSCC cells can be selectively killed by small-molecule inhibitors of USP8 (DUBs-IN-3/compound 22c) and the NEDD8 E1 activating enzyme/CRLs (MLN4924/pevonedistat). A substantial proportion of cSCC cell lines are very highly MLN4924-sensitive. Pathways that respond to defects in proteostasis are involved in the anti-cSCC activity of p97 suppression. Targeting USP8 can reduce the expression of growth factor receptors that participate in cSCC development. EMI1 and CDT2 depletion can selectively cause DNA re-replication and DNA damage in cSCC cells.