Wang Yadong, Li Jiahao, Zheng Haotian, Wang Kai, Ren Xiaoyang, Wang Guanghui, Du Jiajun
Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan, People's Republic of China.
Department of Thoracic Surgery, Shandong Provincial Hospital, Shandong University, Jinan, People's Republic of China.
Cell Death Discov. 2023 Aug 18;9(1):302. doi: 10.1038/s41420-023-01599-4.
Osimertinib is a promising approved third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for treating patients with lung adenocarcinoma (LUAD) harboring EGFR-activating mutations, however, almost all patients develop resistance to Osimertinib eventually limiting the long-term efficacy. Autophagy is a vital cellular recycling process promoting Osimertinib resistance. Identifying accurate and efficient autophagy-regulatory factors is of great significance in reducing Osimertinib resistance. This study identified Cezanne, a member of the ovarian tumor protease (OTU)-deubiquitinating family, as an autophagy regulator. Cezanne was highly expressed in Osimertinib-resistant cells, and Cezanne overexpression promoted Osimertinib resistance, while chloroquine (CQ), an autophagy inhibitor, reverted this process. In the Cezanne-overexpressing cells, autophagy was activated even in the absence of autophagy inducers rapamycin and Earle's Balanced Salt Solution (EBSS). Further study showed that Cezanne stabilized PIK3C3 by deubiquitinating K48-linked ubiquitination at Lysine 322. Surprisingly, as a compensatory mechanism of PI3P generation, PIK3C2A was shown to be upregulated by Cezanne by promoting its transcription in a POLR2A-dependent way. Based on these results, Cezanne also accelerates EGFR recycling which may explain the mechanism mediating Cezanne expression and Osimertinib resistance. In conclusion, this study establishes a new model connecting Cezanne, autophagy, and Osimertinib resistance, opening new avenues to explore the effect of Cezanne and autophagy in LUAD.
奥希替尼是一种有前景的已获批的第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），用于治疗携带EGFR激活突变的肺腺癌（LUAD）患者，然而，几乎所有患者最终都会对奥希替尼产生耐药性，这限制了其长期疗效。自噬是促进奥希替尼耐药性的重要细胞循环过程。识别准确有效的自噬调节因子对于降低奥希替尼耐药性具有重要意义。本研究确定了卵巢肿瘤蛋白酶（OTU）去泛素化家族成员塞尚（Cezanne）为一种自噬调节因子。塞尚在奥希替尼耐药细胞中高表达，过表达塞尚会促进奥希替尼耐药性，而自噬抑制剂氯喹（CQ）可逆转这一过程。在过表达塞尚的细胞中，即使在没有自噬诱导剂雷帕霉素和厄尔平衡盐溶液（EBSS）的情况下，自噬也会被激活。进一步研究表明，塞尚通过去泛素化赖氨酸322处的K48连接泛素化来稳定PIK3C3。令人惊讶的是，作为PI3P产生的一种补偿机制，PIK3C2A被证明可通过以POLR2A依赖的方式促进其转录而被塞尚上调。基于这些结果，塞尚还加速了EGFR循环，这可能解释了介导塞尚表达和奥希替尼耐药性的机制。总之，本研究建立了一个连接塞尚、自噬和奥希替尼耐药性的新模型，为探索塞尚和自噬在LUAD中的作用开辟了新途径。
