KCTD5 regulates Ikaros degradation induced by chemotherapeutic drug etoposide in hematological cells
Author:
Ma Lan12, Yin Changqing1, Zhang Yi1, Li Jie1, Shi Liuzhi3, Zhou Tong1, Huang Xixi1, Liu Yaqi1, Cao Jiawei1, Wu Guang1, Gu Haihua1, He Licai1ORCID
Affiliation:
1. Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medical and Life Science , Wenzhou Medical University , Wenzhou 325035 , China 2. Department of Nephropathy , Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University , Hangzhou 310007 , China 3. Department of Clinical Laboratory , The First Affiliated Hospital of Wenzhou Medical University , Wenzhou 325000 , China
Abstract
Abstract
Therapy-related leukemia carries a poor prognosis, and leukemia after chemotherapy is a growing risk in clinic, whose mechanism is still not well understood. Ikaros transcription factor is an important regulator in hematopoietic cells development and differentiation. In the absence of Ikaros, lymphoid cell differentiation is blocked at an extremely early stage, and myeloid cell differentiation is also significantly affected. In this work, we showed that chemotherapeutic drug etoposide reduced the protein levels of several isoforms of Ikaros including IK1, IK2 and IK4, but not IK6 or IK7, by accelerating protein degradation, in leukemic cells. To investigate the molecular mechanism of Ikaros degradation induced by etoposide, immunoprecipitation coupled with LC-MS/MS analysis was conducted to identify changes in protein interaction with Ikaros before and after etoposide treatment, which uncovered KCTD5 protein. Our further study demonstrates that KCTD5 is the key stabilizing factor of Ikaros and chemotherapeutic drug etoposide induces Ikaros protein degradation through decreasing the interaction of Ikaros with KCTD5. These results suggest that etoposide may induce leukemic transformation by downregulating Ikaros via KCTD5, and our work may provide insights to attenuate the negative impact of chemotherapy on hematopoiesis.
Funder
National Natural Science Foundation of China Natural Science Foundation of Zhejiang Province Key Discipline of Zhejiang Province in Medical Technology
Publisher
Walter de Gruyter GmbH
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