The CUL4B-miR-372/373-PIK3CA-AKT axis regulates metastasis in bladder cancer
The CUL4B-miR-372/373-PIK3CA-AKT axis regulates metastasis in bladder cancer
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CUL4B-miR-372/373-PIK3CA-AKT 轴调节膀胱癌的转移
DOI：
10.1038/s41388-020-1236-1
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发表时间：
2020-03-03
期刊：
影响因子：
8
通讯作者：
Gong, Yaoqin
中科院分区：
文献类型：
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作者：
Liu, Xiaochen;Cui, Jianfeng;Gong, Yaoqin
CUL4B是CUL4B环泛素连接酶(CRL4B)复合体的骨架蛋白，参与多种生物学过程。以前的研究表明，CUL4B在各种实体肿瘤中经常过表达并表现出致癌活性。然而，CUL4B在膀胱癌(BC)中的作用和潜在机制尚不清楚。在这里，我们发现CUL4B的表达水平与BC的恶性程度呈正相关，并且CUL4B可以增强BC细胞的运动性、侵袭性、干性和化疗耐药性。PIK3CA/AKT通路被认为是CUL4B驱动BC细胞致瘤性的关键下游调节因子。此外，我们还证明了CRL4B通过在编码miR-372/373的基因簇上催化H_2AK119的单素化，导致PIK3CA上调和AKT激活，从而在表观遗传学上抑制了miR-372/373的转录。因此，我们的发现确立了CUL4B-miR-372/373-PIK3CA/AKT轴在BC的发病机制中的关键作用，并对BC的预后和治疗具有重要的意义。
CUL4B, which acts as a scaffold protein in CUL4B-RING ubiquitin ligase (CRL4B) complexes, participates in a variety of biological processes. Previous studies have shown that CUL4B is often overexpressed and exhibits oncogenic activities in a variety of solid tumors. However, the roles and the underlying mechanisms of CUL4B in bladder cancer (BC) were poorly understood. Here, we showed that CUL4B levels were overexpressed and positively correlated with the malignancy of BC, and CUL4B could confer BC cells increased motility, invasiveness, stemness, and chemoresistance. The PIK3CA/AKT pathway was identified as a critical downstream mediator of CUL4B-driven oncogenicity in BC cells. Furthermore, we demonstrated that CRL4B epigenetically repressed the transcription of miR-372/373, via catalyzing monoubiquitination of H2AK119 at the gene cluster encoding miR-372/373, leading to upregulation of PIK3CA and activation of AKT. Our findings thus establish a critical role for the CUL4B-miR-372/373-PIK3CA/AKT axis in the pathogenesis of BC and have important prognostic and therapeutic implications in BC.