Hyperthermia promotes degradation of the acute promyelocytic leukemia driver oncoprotein ZBTB16/RARα  

作　　者：Qian-qian Wang Liaqat Hussain Pei-han Yu Chang Yang Chen-ying Zhu Ya-fang Ma Si-chun Wang Tao Yang Yuan-yuan Kang Wen-juan Yu Yasen Maimaitiyiming Hua Naranmandura 

机构地区：[1]Department of Hematology of First Affiliated Hospital,and Department of Public Health,Zhejiang University School of Medicine,Hangzhou 310003,China [2]Zhejiang Province Key Laboratory of Haematology Oncology Diagnosis and Treatment,Hangzhou 310003,China [3]Cancer Center,Zhejiang University,Hangzhou 310058,China [4]Faculty of Pharmaceutical Sciences,Government College University,Faisalabad 38000,Pakistan [5]Department of Hematology,First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310003,China [6]Department of Neurobiology,NHC and CAMS Key Laboratory of Medical Neurobiology,School of Brain Science and Brain Medicine,and MOE Frontier Science Center for Brain Science and Brain-machineIntegration,Zhejiang University School of Medicine,Hangzhou 310031,China

出　　处：《Acta Pharmacologica Sinica》2023年第4期822-831,共10页中国药理学报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(No.81872942,82003875,82000155,82000145,82200160);the China Postdoctoral Science Foundation(No.2021M702875,2021M702877);the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang,Grant/Award Number:2020R01006.

摘　　要：The acute promyelocytic leukemia(APL)driver ZBTB16/RARαis generated by the t(11;17)(q23;q21)chromosomal translocation,which is resistant to combined treatment of all-trans retinoic 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/RARαprotein 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℃)rapidly destabilized the ZBTB16/RARαfusion 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 RARαproteins,suggesting a specific thermal sensitivity of the ZBTB16/RARαfusion protein.Importantly,we found that the destabilization of ZBTB16/RARαwas 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/RARαfusion 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.

关 键 词：acute promyelocytic leukemia ZBTB16/RARαfusion protein HYPERTHERMIA PROTEOLYSIS nuclear receptor corepressors ARSENICALS 

分 类 号：R285.5[医药卫生—中药学]