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Mol. Cells

Published online January 24, 2023

© The Korean Society for Molecular and Cellular Biology

SKP2 Contributes to AKT Activation by Ubiquitination Degradation of PHLPP1, Impedes Autophagy, and Facilitates the Survival of Thyroid Carcinoma

Yuan Shao1,4 , Wanli Ren1,4 , Hao Dai1 , Fangli Yang1 , Xiang Li1 , Shaoqiang Zhang1 , Junsong Liu1 , Xiaobao Yao1 , Qian Zhao1 , Xin Sun2 , Zhiwei Zheng3 , and Chongwen Xu1,*

1Department of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xi’An Jiaotong University, Xi’an, China, 2Department of Thoracic Surgery, The First Affiliated Hospital of Xi’An Jiaotong University, Xi’an, China, 3The Third Ward of General Surgery Department, Rizhao People’s Hospital, Rizhao, China, 4These authors contributed equally to this work.

Correspondence to : henao22@xjtu.edu.cn

Received: September 21, 2021; Revised: February 18, 2022; Accepted: March 31, 2022

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

Abstract

Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid carcinoma. Despite a good prognosis, approximately a quarter of PTC patients are likely to relapse. Previous reports suggest an association between S-phase kinase-associated protein 2 (SKP2) and the prognosis of thyroid cancer. SKP1 is related to apoptosis of PTC cells; however, its role in PTC remains largely elusive. This study aimed to understand the expression and molecular mechanism of SKP2 in PTC. SKP2 expression was upregulated in PTC tissues and closely associated with clinical diagnosis. In vitro and in vivo knockdown of SKP2 expression in PTC cells suppressed cell growth and proliferation and induced apoptosis. SKP2 depletion promoted cell autophagy under glucose deprivation. SKP2 interacted with PH domain leucine-rich repeat protein phosphatase-1 (PHLPP1), triggering its degradation by ubiquitination. Furthermore, SKP2 activates the AKT-related pathways via PHLPP1, which leads to the cytoplasmic translocation of SKP2, indicating a reciprocal regulation between SKP2 and AKT. In conclusion, the upregulation of SKP2 leads to PTC proliferation and survival, and the regulatory network among SKP2, PHLPP1, and AKT provides novel insight into the molecular basis of SKP2 in tumor progression.

Keywords AKT, molecular mechanism, papillary thyroid carcinoma, PH domain leucine-rich repeat protein phosphatase-1, S-phase kinase-associated protein 2

Article

On-line First

Mol. Cells

Published online January 24, 2023

Copyright © The Korean Society for Molecular and Cellular Biology.

SKP2 Contributes to AKT Activation by Ubiquitination Degradation of PHLPP1, Impedes Autophagy, and Facilitates the Survival of Thyroid Carcinoma

Yuan Shao1,4 , Wanli Ren1,4 , Hao Dai1 , Fangli Yang1 , Xiang Li1 , Shaoqiang Zhang1 , Junsong Liu1 , Xiaobao Yao1 , Qian Zhao1 , Xin Sun2 , Zhiwei Zheng3 , and Chongwen Xu1,*

1Department of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xi’An Jiaotong University, Xi’an, China, 2Department of Thoracic Surgery, The First Affiliated Hospital of Xi’An Jiaotong University, Xi’an, China, 3The Third Ward of General Surgery Department, Rizhao People’s Hospital, Rizhao, China, 4These authors contributed equally to this work.

Correspondence to:henao22@xjtu.edu.cn

Received: September 21, 2021; Revised: February 18, 2022; Accepted: March 31, 2022

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

Abstract

Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid carcinoma. Despite a good prognosis, approximately a quarter of PTC patients are likely to relapse. Previous reports suggest an association between S-phase kinase-associated protein 2 (SKP2) and the prognosis of thyroid cancer. SKP1 is related to apoptosis of PTC cells; however, its role in PTC remains largely elusive. This study aimed to understand the expression and molecular mechanism of SKP2 in PTC. SKP2 expression was upregulated in PTC tissues and closely associated with clinical diagnosis. In vitro and in vivo knockdown of SKP2 expression in PTC cells suppressed cell growth and proliferation and induced apoptosis. SKP2 depletion promoted cell autophagy under glucose deprivation. SKP2 interacted with PH domain leucine-rich repeat protein phosphatase-1 (PHLPP1), triggering its degradation by ubiquitination. Furthermore, SKP2 activates the AKT-related pathways via PHLPP1, which leads to the cytoplasmic translocation of SKP2, indicating a reciprocal regulation between SKP2 and AKT. In conclusion, the upregulation of SKP2 leads to PTC proliferation and survival, and the regulatory network among SKP2, PHLPP1, and AKT provides novel insight into the molecular basis of SKP2 in tumor progression.

Keywords: AKT, molecular mechanism, papillary thyroid carcinoma, PH domain leucine-rich repeat protein phosphatase-1, S-phase kinase-associated protein 2

Mol. Cells
Mar 31, 2023 Vol.46 No.3, pp. 131~189
COVER PICTURE
The physiologically important cytoprotective signaling in normal cells (background area in turquoise) mediated by NRF2 (blue chain) is often hijacked by cancer cells (red ball) in the tumor microenvironment (yellow area). However, the differential roles of NRF2 throughout the multistage carcinogenesis remains largely unresolved (white-colored overlapping misty areas).

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