Deubiquitinase USP48 promotes ATRA-induced granulocytic differentiation of acute promyelocytic leukemia cells

Li,Lianlian; Wang,Yong; Zhang,Xiaoyu; Song,Guanhua; Guo,Qiang; Zhang,Zhiyong; Diao,Yutao; Yin,Haipeng; Liu,Hongyan; Jiang,Guosheng

doi:10.3892/ijo.2018.4440

Deubiquitinase USP48 promotes ATRA-induced granulocytic differentiation of acute promyelocytic leukemia cells

Authors:
- Lianlian Li
- Yong Wang
- Xiaoyu Zhang
- Guanhua Song
- Qiang Guo
- Zhiyong Zhang
- Yutao Diao
- Haipeng Yin
- Hongyan Liu
- Guosheng Jiang
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Affiliations: Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong 250062, P.R. China, Shandong Xinchuang Biotechnology Co., Ltd., Jinan, Shandong 250102, P.R. China
Published online on: June 13, 2018 https://doi.org/10.3892/ijo.2018.4440
Pages: 895-903

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Abstract

All-trans retinoic acid (ATRA) has been used for the treatment of acute promyelocytic leukemia (APL). However, its molecular mechanisms of action are unclear. Ubiquitin-specific protease 48 (USP48) is a deubiquitinase enzyme that can post-translationally remove ubiquitin molecules from substrates. In the present study, the role of USP48 in ATRA-induced differentiation of APL cells was studied. The expression of USP48 decreased following ATRA treatment. Functionally, overexpression of USP48 using electroporation-mediated delivery inhibited the proliferation of APL cells and promoted ATRA-mediated differentiation. The inverse observations were made upon siRNA-mediated knockdown of USP48. Furthermore, the expression of USP48 was increased in the nucleus upon ATRA exposure for ≤24 h, suggesting that USP48 was translocated into the nucleus. Interestingly, regulation of p65, a substrate of USP48, did not contribute to the downstream mechanism of ATRA-induced differentiation of APL cells. In addition, upstream mechanistic studies demonstrated that the expression of USP48 was regulated by microRNA-301a-3p. In conclusion, the present study highlights the function of USP48 in the ATRA-induced granulocytic differentiation of APL cells and provides a theoretical basis for identifying novel targets for differentiation therapy of APL.

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