Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2022.066
PRR16/Largen Induces Epithelial-Mesenchymal Transition through the Interaction with ABI2 Leading to the Activation of ABL1 Kinase
Gyeoung Jin Kang1,†, Jung Ho Park2,†, Hyun Ji Kim2, Eun Ji Kim1, Boram Kim2, Hyun Jung Byun2, Lu Yu2, Tuan Minh Nguyen2, Thi Ha Nguyen2, Kyung Sung Kim2, Hiệu Phùng Huy2, Mostafizur Rahman2, Ye Hyeon Kim2, Ji Yun Jang2,3, Mi Kyung Park3, Ho Lee3, Chang Ick Choi2, Kyeong Lee2, Hyo Kyung Han2, Jungsook Cho2, Seung Bae Rho3,* and Chang Hoon Lee2,*
1Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA
2College of Pharmacy, Dongguk University, Goyang 10326,
3National Cancer Center, Goyang 10408, Republic of Korea
The first two authors contributed equally to this work.
*E-mail: sbrho@ncc.re.kr (Rho SB), uatheone@dongguk.edu (Lee CH)
Tel: +82-31-920-2383 (Rho SB), +82-31-961-5213 (Lee CH)
Fax: +82-31-920-2399 (Rho, SB), +82-31-961-5206 (Lee CH)
Received: May 15, 2022; Revised: May 28, 2022; Accepted: June 1, 2022; Published online: June 20, 2022.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Advanced or metastatic breast cancer affects multiple organs and is a leading cause of cancer-related death. Cancer metastasis is associated with epithelial-mesenchymal metastasis (EMT). However, the specific signals that induce and regulate EMT in carcinoma cells remain unclear. PRR16/Largen is a cell size regulator that is independent of mTOR and Hippo signalling pathways. However, little is known about the role PRR16 plays in the EMT process. We found that the expression of PRR16 was increased in mesenchymal breast cancer cell lines. PRR16 overexpression induced EMT in MCF7 breast cancer cells and enhances migration and invasion. To determine how PRR16 induces EMT, the binding proteins for PRR16 were screened, revealing that PRR16 binds to Abl interactor 2 (ABI2). We then investigated whether ABI2 is involved in EMT. Gene silencing of ABI2 induces EMT, leading to enhanced migration and invasion. ABI2 is a gene that codes for a protein that interacts with ABL proto-oncogene 1 (ABL1) kinase. Therefore, we investigated whether the change in ABI2 expression affected the activation of ABL1 kinase. The knockdown of ABI2 and PRR16 overexpression increased the phosphorylation of Y412 in ABL1 kinase. Our results suggest that PRR16 may be involved in EMT by binding to ABI2 and interfering with its inhibition of ABL1 kinase. This indicates that ABL1 kinase inhibitors may be potential therapeutic agents for the treatment of PRR16-related breast cancer.
Keywords: PRR16, ABI2, ABL1 kinase, Epithelial-mesenchymal transition, Breast cancer


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