Deubiquitylase USP12 induces pro-survival autophagy and bortezomib resistance in multiple myeloma by stabilizing HMGB1
Deubiquitylase USP12 induces pro-survival autophagy and bortezomib resistance in multiple myeloma by stabilizing HMGB1
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DOI：
10.1038/s41388-021-02167-9
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发表时间：
2022-01-07
期刊：
影响因子：
8
通讯作者：
Liu, Jing
中科院分区：
文献类型：
--
作者：
Li, Hui;Roy, Mridul;Liu, Jing
尽管建立了新的治疗干预措施，多发性骨髓瘤（MM）仍然是不可治愈的，由于耐药性的发展和随后的复发，这是由于致癌途径，如自噬的激活。去泛素化酶（DUBs）是克服对基于蛋白酶体转运蛋白的治疗的抗性的有希望的靶点。泛素特异性蛋白酶-12（USP 12）是一种DUB，在几种癌症中具有已知的预后价值。我们发现，骨髓瘤患者样本中的USP 12蛋白水平显著高于非癌症人类样本。USP 12的耗尽抑制细胞生长和克隆形成并抑制自噬。机制研究表明，USP 12与关键的自噬介质HMGB 1（高迁移率族蛋白-1）蛋白相互作用，去泛素化并稳定化。USP 12的敲除降低了MM中HMGB 1的水平并抑制了HMGB 1介导的自噬。此外，在硼替佐米（BTZ）抗性MM细胞系中，与USP 12/HMGB 1相关的基础自噬活性升高。USP 12耗竭，伴随着HMGB 1表达的减少，抑制了自噬并增加了耐药细胞对BTZ的敏感性。总的来说，我们的研究结果已经确定了去泛素化酶USP 12通过稳定HMGB 1在MM中的促生存自噬和由此产生的BTZ抗性中的重要作用，这表明USP 12/HMGB 1轴可能被追求为人类MM的潜在诊断和治疗靶点。
Despite the establishment of novel therapeutic interventions, multiple myeloma (MM) remains invariably incurable due to development of drug resistance and subsequent relapse, which are attributed to activation of oncogenic pathways such as autophagy. Deubiquitinating enzymes (DUBs) are promising targets to overcome resistance to proteasome inhibitor-based treatment. Ubiquitin-specific protease-12 (USP12) is a DUB with a known prognostic value in several cancers. We found that USP12 protein levels were significantly higher in myeloma patient samples than in non-cancerous human samples. Depletion of USP12 suppressed cell growth and clonogenicity and inhibited autophagy. Mechanistic studies showed that USP12 interacted with, deubiquitylated and stabilized the critical autophagy mediator HMGB1 (high mobility group box-1) protein. Knockdown of USP12 decreased the level of HMGB1 and suppressed HMGB1-mediated autophagy in MM. Furthermore, basal autophagy activity associated with USP12/HMGB1 was elevated in bortezomib (BTZ)-resistant MM cell lines. USP12 depletion, concomitant with a reduced expression of HMGB1, suppressed autophagy and increased the sensitivity of resistant cells to BTZ. Collectively, our findings have identified an important role of the deubiquitylase USP12 in pro-survival autophagy and resultant BTZ resistance in MM by stabilizing HMGB1, suggesting that the USP12/HMGB1 axis might be pursued as a potential diagnostic and therapeutic target in human MM.