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

Qian-qian Wang1,2,3, Liaqat Hussain4, Pei-han Yu1, Chang Yang1, Chen-ying Zhu1, Ya-fang Ma5, Si-chun Wang1, Tao Yang1, Yuan-yuan Kang1, Wen-juan Yu5, Yasen Maimaitiyiming1,6, Hua Naranmandura1,2,3
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-machine Integration, Zhejiang University School of Medicine, Hangzhou 310031, China
Correspondence to: Yasen Maimaitiyiming:, Hua Naranmandura:,
DOI: 10.1038/s41401-022-01001-6
Received: 6 June 2022
Accepted: 13 September 2022
Advance online: 10 October 2022


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-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/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.
Keywords: acute promyelocytic leukemia; ZBTB16/RARα fusion protein; hyperthermia; proteolysis; nuclear receptor corepressors; arsenicals

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