Hyperthermia promotes degradation of the acute promyelocytic leukemia driver oncoprotein ZBTB16/RARα
Hyperthermia promotes degradation of the acute promyelocytic leukemia driver oncoprotein ZBTB16/RARα
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DOI：
10.1038/s41401-022-01001-6
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发表时间：
2022-10
影响因子：
8.2
通讯作者：
Qianqian Wang;Liaqat Hussain;Pei-han Yu;Chang Yang;Chengfang Zhu;Yaofang Ma;Si-Chun Wang;Tao T. Yang;Yuan-Yuan Kang-Yuan;Wenjuan Yu;Yasen Maimaitiyiming;Hua Naranmandura
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作者：
Qianqian Wang;Liaqat Hussain;Pei-han Yu;Chang Yang;Chengfang Zhu;Yaofang Ma;Si-Chun Wang;Tao T. Yang;Yuan-Yuan Kang-Yuan;Wenjuan Yu;Yasen Maimaitiyiming;Hua Naranmandura
急性早幼粒细胞白血病ZBTB16/RARα是由t(11；17)(q23；q21)染色体易位所致，对全反式维甲酸、三氧化二砷联合治疗或常规化疗耐药，存活率极低。在本研究中，我们研究了高温对ZBTB16/RARα癌基因融合蛋白的影响，以探索一种潜在的治疗方法。我们发现在HeLa细胞中表达的Z/R融合蛋白对ATO、ATRA和常规化疗药物具有耐药性。然而，轻度高温(42 °C)迅速破坏了在HeLa、293T和OCI-AML3细胞中表达的ZBTB 16/RARα融合蛋白的稳定性，随后发生了强烈的泛素化和蛋白酶体降解。相比之下，高温对正常(即未融合)的ZBTB 16和RARα蛋白没有影响，表明ZBTB 16/RARα融合蛋白具有特定的热敏感性。重要的是，我们发现ZBT16/RARα的失稳是高温导致癌基因融合蛋白降解的第一步，这一过程可以被核受体辅阻遏子结合位点的缺失或核受体辅阻遏子的敲除所阻断。此外，SIHA2被鉴定为参与高温诱导ZBTB 16/RARα泛素化的E3连接酶。总之，这些结果表明，热疗可以有效地破坏ZBTB 16/RARα融合蛋白的稳定性，并以一种NCoR依赖的方式随后降解ZBTB 16/RARα融合蛋白，这表明一种基于热的治疗策略可能会改善临床上难治性ZBTB 16/RAR APL患者的预后。
The acute promyelocytic leukemia (APL) driver ZBTB16/RARα is generated by the t(11;17) (q23;q21) chromosomal translocation, which is resistant to combined treatment of all-transretinoic acid (ATRA) and arsenic trioxide (ATO) or conventional chemotherapy, resulting in extremely low survival rates. In the current study, we investigated the effects of hyperthermia on the oncogenic fusion ZBTB16/RARα protein to explore a potential therapeutic approach for this variant APL. We showed that Z/R fusion protein expressed in HeLa cells was resistant to ATO, ATRA, and conventional chemotherapeutic agents. However, mild hyperthermia (42 °C) rapidly destabilized the ZBTB16/RARα fusion protein expressed in HeLa, 293T, and OCI-AML3 cells, followed by robust ubiquitination and proteasomal degradation. In contrast, hyperthermia did not affect the normal (i.e., unfused) ZBTB16 and RARα proteins, suggesting a specific thermal sensitivity of the ZBTB16/RARα fusion protein. Importantly, we found that the destabilization of ZBTB16/RARα was the initial step for oncogenic fusion protein degradation by hyperthermia, which could be blocked by deletion of nuclear receptor corepressor (NCoR) binding sites or knockdown of NCoRs. Furthermore, SIAH2 was identified as the E3 ligase participating in hyperthermia-induced ubiquitination of ZBTB16/RARα. In short, these results demonstrate that hyperthermia could effectively destabilize and subsequently degrade the ZBTB16/RARα fusion protein in an NCoR-dependent manner, suggesting a thermal-based therapeutic strategy that may improve the outcome in refractory ZBTB16/RARα-driven APL patients in the clinic.