DKK1 Suppresses WWP2 to Enhance Bortezomib Resistance in Multiple Myeloma via Regulating GLI2 Ubiquitination.
DKK1 Suppresses WWP2 to Enhance Bortezomib Resistance in Multiple Myeloma via Regulating GLI2 Ubiquitination.
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DOI：
10.1093/carcin/bgab086
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发表时间：
2021-09
期刊：
影响因子：
4.7
通讯作者：
Qi-guo Zhang;Wenyu Gong;Hongyan Wu;Jing Wang;Qichuan Jin;Chun Lin;Shiyun Xu-;Wenqiang Bao;Yin Wang;Jing Wu;Shanshan Feng;Changzhi Zhao;Bing Chen;Zhiqiang Liu
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文献类型：
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作者：
Qi-guo Zhang;Wenyu Gong;Hongyan Wu;Jing Wang;Qichuan Jin;Chun Lin;Shiyun Xu-;Wenqiang Bao;Yin Wang;Jing Wu;Shanshan Feng;Changzhi Zhao;Bing Chen;Zhiqiang Liu
硼替佐米为基础的化疗代表了多发性骨髓瘤（MM）最流行的方案，而获得性耐药仍然是一个主要障碍。骨髓瘤细胞通常产生过量的dickkopf-1（DKK 1），引起骨髓瘤骨病（MBD）。然而，DKK 1在MM细胞进展和硼替佐米反应性中的作用和机制仍不清楚。在目前的研究中，我们发现WWP 2，一种E3泛素蛋白连接酶，在硼替佐米耐药细胞中下调沿着DKK 1高表达。进一步的研究表明，WWP 2是Wnt/β-catenin信号通路的直接靶点，DKK 1通过经典的Wnt信号通路抑制WWP 2的表达。我们进一步鉴定了WWP 2介导了刺猬（Hh）通路的主要转录因子GLI 2的泛素化和降解。因此，DKK 1诱导的WWP 2下调改善了GLI 2的稳定性和Hh信号通路的激活，有助于MM细胞对硼替佐米的抗性。临床数据还证实，WWP 2表达与MM患者的治疗反应和临床结局相关。在体外和体内，WWP 2过表达限制MM进展并增强细胞对硼替佐米治疗的敏感性。综上所述，我们的研究结果表明，DKK 1通过下调WWP 2和激活Hh通路促进MM中硼替佐米耐药性的产生。因此，DKK 1-WWP 2-GLI 2轴的操作可能使骨髓瘤细胞对蛋白酶体抑制剂敏感。
Bortezomib-based chemotherapy represents the most prevalent regimens for multiple myeloma (MM), whereas acquired drug resistance remains a major obstacle. Myeloma cells often produce excessive amount of dickkopf-1 (DKK1), giving rise to myeloma bone disease (MBD). However, it remains obscure about the effects and mechanisms of DKK1 in the progression and bortezomib responsiveness of MM cells. In the current study, we found WWP2, an E3 ubiquitin-protein ligase, was downregulated in the bortezomib-resistant cells along with high expression of DKK1. Further investigation revealed that WWP2 was a direct target of Wnt/β-catenin signaling pathway, and DKK1 suppressed the expression of WWP2 via canonical Wnt signaling. We further identified that WWP2 mediated the ubiquitination and degradation of GLI2, a main transcriptional factor of the hedgehog (Hh) pathway. Therefore, DKK1-induced WWP2 downregulation improved GLI2 stability and activation of Hh signaling pathway, contributing to the resistance to bortezomib of MM cells. Clinical data also validated that WWP2 expression was associated with the treatment response and clinic outcomes of MM patients. WWP2 overexpression restricted MM progression and enhanced cell sensitivity to bortezomib treatment in vitro and in vivo. Taken together, our findings demonstrate that DKK1 facilitates the generation of bortezomib resistance in MM via downregulating WWP2 and activating Hh pathway. Thus, the manipulation of DKK1-WWP2-GLI2 axis might sensitize myeloma cells to proteasome inhibitors.