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Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy

1
Department of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan
2
Health Administration Centre, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan
3
Division of Histology and Neuroanatomy, Department of Anatomy and Physiology, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan
4
Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan
*
Author to whom correspondence should be addressed.
Present address: Department of Internal Medicine, Musashimurayama Hospital, 1-1-5 Enoki, Musashimurayama, Tokyo 208-0022, Japan.
Cells 2020, 9(1), 218; https://doi.org/10.3390/cells9010218
Received: 24 November 2019 / Revised: 10 January 2020 / Accepted: 11 January 2020 / Published: 15 January 2020
(This article belongs to the Section Autophagy)
PDCD4 (programmed cell death 4) is a tumor suppressor that plays a crucial role in multiple cellular functions, such as the control of protein synthesis and transcriptional control of some genes, the inhibition of cancer invasion and metastasis. The expression of this protein is controlled by synthesis, such as via transcription and translation, and degradation by the ubiquitin-proteasome system. The mitogens, known as tumor promotors, EGF (epidermal growth factor) and TPA (12-O-tetradecanoylphorbol-13-acetate) stimulate the degradation of PDCD4 protein. However, the whole picture of PDCD4 degradation mechanisms is still unclear, we therefore investigated the relationship between PDCD4 and autophagy. The proteasome inhibitor MG132 and the autophagy inhibitor bafilomycin A1 were found to upregulate the PDCD4 levels. PDCD4 protein levels increased synergistically in the presence of both inhibitors. Knockdown of p62/SQSTM1 (sequestosome-1), a polyubiquitin binding partner, also upregulated the PDCD4 levels. P62 and LC3 (microtubule-associated protein 1A/1B-light chain 3)-II were co-immunoprecipitated by an anti-PDCD4 antibody. Colocalization particles of PDCD4, p62 and the autophagosome marker LC3 were observed and the colocalization areas increased in the presence of autophagy and/or proteasome inhibitor(s) in Huh7 cells. In ATG (autophagy related) 5-deficient Huh7 cells in which autophagy was impaired, the PDCD4 levels were increased at the basal levels and upregulated in the presence of autophagy inhibitors. Based on the above findings, we concluded that after phosphorylation in the degron and ubiquitination, PDCD4 is degraded by both the proteasome and autophagy systems. View Full-Text
Keywords: autophagy; p62/SQSTM1; PDCD4; proteasome; ubiquitination autophagy; p62/SQSTM1; PDCD4; proteasome; ubiquitination
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Manirujjaman, M.; Ozaki, I.; Murata, Y.; Guo, J.; Xia, J.; Nishioka, K.; Perveen, R.; Takahashi, H.; Anzai, K.; Matsuhashi, S. Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy. Cells 2020, 9, 218.

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