LACTB suppresses melanoma progression by attenuating PP1A and YAP interaction
LACTB suppresses melanoma progression by attenuating PP1A and YAP interaction
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LACTB 通过减弱 PP1A 和 YAP 相互作用来抑制黑色素瘤进展
DOI：
10.1016/j.canlet.2021.02.022
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发表时间：
2021-03-09
期刊：
影响因子：
9.7
通讯作者：
Jia, Renbing
中科院分区：
文献类型：
--
作者：
Ma, Yawen;Wang, Lihua;Jia, Renbing
在晚期黑色素瘤，特别是葡萄膜源性黑色素瘤的治疗方面，进展非常有限。内酰胺酶（Lactamase - β， LACTB）是一种新的肿瘤抑制因子；然而，其在黑色素瘤中的生物学功能尚不清楚。本研究表明，在黑色素瘤组织和细胞系中，LACTB的表达水平明显降低。在体外，过表达LACTB可抑制黑色素瘤细胞的增殖、迁移和侵袭。在机制上，LACTB抑制yes-associated protein （YAP）的活性。我们发现磷酸化-YAP（丝氨酸127）水平在LACTB过表达时增加，这阻止了YAP向细胞核的易位。此外，LACTB可以直接结合PP1A，减弱PP1A与YAP之间的相互作用，导致YAP去磷酸化和失活以lats1不依赖的方式减少。此外，转染磷酸化缺陷的YAP突变体逆转了lactb诱导的肿瘤抑制。在上游，我们证明SOX10与LACTB启动子结合并负调控其转录。在体内，过表达LACTB还能抑制MUM2B葡萄膜黑色素瘤细胞的致瘤性和肺转移。综上所述，我们的研究结果表明，一种新的SOX10/LACTB/PP1A信号级联可使YAP失活并调节黑色素瘤的进展，为黑色素瘤治疗提供了新的治疗靶点。
Very limited progress has been made in the management of advanced melanoma, especially melanoma of uveal origin. Lactamase beta (LACTB) is a novel tumor suppressor; however, its biological function in melanoma remains unknown. Herein we demonstrated markedly lower LACTB expression levels in melanoma tissues and cell lines. Overexpression of LACTB suppressed the proliferation, migration and invasion of melanoma cells in vitro. Mechanistically, LACTB inhibited the activity of yes-associated protein (YAP). We showed that the level of phospho-YAP (Serine 127) was increased upon LACTB overexpression, which prevented the translocation of YAP to the nucleus. Further, LACTB could directly bind to PP1A and attenuate the interaction between PP1A and YAP, resulting in decreased YAP dephosphorylation and inactivation in a LATS1-independent manner. Additionally, transfection of phosphorylation-defective YAP mutants reversed LACTB-induced tumor suppression. Upstream, we demonstrated that SOX10 binds to the LACTB promoter and negatively regulates its transcription. Overexpression of LACTB also suppressed the tumorigenicity and lung metastasis of MUM2B uveal melanoma cells in vivo. Taken together, our findings indicate a novel SOX10/LACTB/PP1A signaling cascade that renders YAP inactive and modulates melanoma progression, offering a new therapeutic target for melanoma treatment.