- Title
- KDM6A promotes imatinib resistance through YY1-mediated transcriptional upregulation of TRKA independently of its demethylase activity in chronic myelogenous leukemia
- Creator
- Zhang, Chengwan; Shen, Li; Wei, Dongping; Thorne, Rick F.; Zhang, Xu Dong; Yu, Liang; Chen, Song; Zhu, Yifu; Xu, Ran; Deng, Zhikui; Liu, Xiaoning; Ding, Yihan; Wang, Chunling; Shi, Yuye; Bei, Liye
- Relation
- Theranostics Vol. 11, Issue 6, p. 2691-2705
- Publisher Link
- http://dx.doi.org/10.7150/thno.50571
- Publisher
- Ivyspring International
- Resource Type
- journal article
- Date
- 2021
- Description
- Rationale: Despite landmark therapy of chronic myelogenous leukemia (CML) with tyrosine kinase inhibitors (TKIs), drug resistance remains problematic. Cancer pathogenesis involves epigenetic dysregulation and in particular, histone lysine demethylases (KDMs) have been implicated in TKI resistance. We sought to identify KDMs with altered expression in CML and define their contribution to imatinib resistance. Methods: Bioinformatics screening compared KDM expression in CML versus normal bone marrow with shRNA knockdown and flow cytometry used to measure effects on imatinib-induced apoptosis in K562 cells. Transcriptomic analyses were performed against KDM6A CRISPR knockout/shRNA knockdown K562 cells along with gene rescue experiments using wildtype and mutant demethylase-dead KDM6A constructs. Co-immunoprecipitation, luciferase reporter and ChIP were employed to elucidate mechanisms of KDM6A-dependent resistance. Results: Amongst five KDMs upregulated in CML, only KDM6A depletion sensitized CML cells to imatinib-induced apoptosis. Re-introduction of demethylase-dead KDM6A as well as wild-type KDM6A restored imatinib resistance. RNA-seq identified NTRK1 gene downregulation after depletion of KDM6A. Moreover, NTRK1 expression positively correlated with KDM6A in a subset of clinical CML samples and KDM6A knockdown in fresh CML isolates decreased NTRK1 encoded protein (TRKA) expression. Mechanistically, KDM6A was recruited to the NTRK1 promoter by the transcription factor YY1 with subsequent TRKA upregulation activating down-stream survival pathways to invoke imatinib resistance. Conclusion: Contrary to its reported role as a tumor suppressor and independent of its demethylase function, KDM6A promotes imatinib-resistance in CML cells. The identification of the KDM6A/YY1/TRKA axis as a novel imatinib-resistance mechanism represents an unexplored avenue to overcome TKI resistance in CML.
- Subject
- KDM6A/UTX; YY1; NTRK1/TRKA; CML; imatinib resistance; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1455776
- Identifier
- uon:45133
- Identifier
- ISSN:1838-7640
- Rights
- This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
- Language
- eng
- Full Text
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