miR-221/222 induce instability of p53 By downregulating deubiquitinase YOD1 in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by the impaired differentiation and uncontrolled proliferation of myeloid blasts. Tumor suppressor p53 is often downregulated in AML cells via ubiquitination-mediated degradation. While the role of E3 ligase MDM2 in p53 ubiquitination is well-accepted, little is known about the involvement of deubiquitinases (DUBs). Herein, we found that the expression of YOD1, among several DUBs, is substantially reduced in blood cells from AML patients. We identified that YOD1 deubiqutinated and stabilized p53 through interaction via N-terminus of p53 and OTU domain of YOD1. In addition, expression levels of YOD1 were suppressed by elevated miR-221/222 in AML cells through binding to the 3' untranslated region of YOD1, as verified by reporter gene assays. Treatment of cells with miR-221/222 mimics and inhibitors yielded the expected effects on YOD1 expressions, in agreement with the negative correlation observed between the expression levels of miR-221/222 and YOD1 in AML cells. Finally, overexpression of YOD1 stabilized p53, upregulated pro-apoptotic p53 downstream genes, and increased the sensitivity of AML cells to FLT3 inhibitors remarkably. Collectively, our study identified a pathway connecting miR-221/222, YOD1, and p53 in AML. Targeting miR-221/222 and stimulating YOD1 activity may improve the therapeutic effects of FLT3 inhibitors in patients with AML. © 2023. The Author(s).

Citation

Han Zhong Pei, Zhiyong Peng, Xiaomei Zhuang, Xiaobo Wang, Bo Lu, Yao Guo, Yuming Zhao, Dengyang Zhang, Yunjun Xiao, Tianshun Gao, Liuting Yu, Chunxiao He, Shunjie Wu, Suk-Hwan Baek, Zhizhuang Joe Zhao, Xiaojun Xu, Yun Chen. miR-221/222 induce instability of p53 By downregulating deubiquitinase YOD1 in acute myeloid leukemia. Cell death discovery. 2023 Jul 15;9(1):249

PMID: 37454155

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