Discovery of the Oncogenic Parp1, a Target of bcr-abl and a Potential Therapeutic, in mir-181a/PPFIA1 Signaling Pathway

Chunming Gu; Yanjun Liu; Zhao Yin; Juhua Yang; Guiping Huang; Xuejiao Zhu; Yumin Li; Jia Fei

doi:10.1016/j.omtn.2019.01.015

Discovery of the Oncogenic Parp1, a Target of bcr-abl and a Potential Therapeutic, in mir-181a/PPFIA1 Signaling Pathway

Mol Ther Nucleic Acids. 2019 Jun 7:16:1-14. doi: 10.1016/j.omtn.2019.01.015. Epub 2019 Feb 8.

Authors

Chunming Gu¹, Yanjun Liu², Zhao Yin¹, Juhua Yang², Guiping Huang², Xuejiao Zhu², Yumin Li², Jia Fei³

Affiliations

¹ Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China; Insititute of Chinese Integrative Medicine, Medical College of Jinan University, Guangzhou 510632, China; Engineering Technology Research Center of Drug Development for Small Nucleic Acid, Guangdong, China; Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou, China.
² Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China; Engineering Technology Research Center of Drug Development for Small Nucleic Acid, Guangdong, China; Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou, China.
³ Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China; Insititute of Chinese Integrative Medicine, Medical College of Jinan University, Guangzhou 510632, China; Engineering Technology Research Center of Drug Development for Small Nucleic Acid, Guangdong, China; Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou, China. Electronic address: efeijia@163.com.

Abstract

miR-181a is downregulated in leukemia and affects its progression, drug resistance, and prognosis. However, the exact mechanism of its targets in leukemia, particularly in chronic myelogenous leukemia (CML), has not previously been established. Here, we use a multi-omics approach to demonstrate that protein tyrosine phosphatase, receptor type, f polypeptide, leukocyte common antigen (LAR) interacting protein (liprin), alpha 1 (PPFIA1) is a direct target for miR-181a in CML. Phospho-array assay shows that multiple phosphorylated proteins, particularly KIT signaling molecules, were downregulated in PPFIA1 inhibition. Additionally, PPFIA1 bound PARP1, a common molecule downstream of both PPFIA1 and BCR/ABL, to upregulate KIT protein through activation of nuclear factor kappa B (NF-κB)-P65 expression. Targeted inhibition of PPFIA1 and PARP1 downregulated c-KIT level, inhibited CML cell growth, and prolonged mouse survival. Overall, we report a critical regulatory miR-181a/PPFIA1/PARP1/NF-κB-P65/KIT axis in CML, and our preclinical study supports that targeted PPFIA1 and PARP1 may serve as a potential CML therapy.

Keywords: CML; PARP1; PPFIA1; miR-181a; multi-omics; siRNA treatment.