Ubiquitin-Specific Protease 29 Regulates Cdc25A-Mediated Tumorigenesis.

Arun Pandian Chandrasekaran,Apoorvi Tyagi,Soumyadip Das,Bharathi Suresh,Sang Hyeon Woo,Suresh Ramakrishna,Neha Sarodaya,Kye-Seong Kim,Byung Ho Rhie,Na Re Ko,Seung Jun Oh

doi:10.3390/ijms22115766

Abstract

Cell division cycle 25A (Cdc25A) is a dual-specificity phosphatase that is overexpressed in several cancer cells and promotes tumorigenesis. In normal cells, Cdc25A expression is regulated tightly, but the changes in expression patterns in cancer cells that lead to tumorigenesis are unknown. In this study, we showed that ubiquitin-specific protease 29 (USP29) stabilized Cdc25A protein expression in cancer cell lines by protecting it from ubiquitin-mediated proteasomal degradation. The presence of USP29 effectively blocked polyubiquitination of Cdc25A and extended its half-life. CRISPR-Cas9-mediated knockdown of USP29 in HeLa cells resulted in cell cycle arrest at the G0/G1 phase. We also showed that USP29 knockdown hampered Cdc25A-mediated cell proliferation, migration, and invasion of cancer cells in vitro. Moreover, NSG nude mice transplanted with USP29-depleted cells significantly reduced the size of the tumors, whereas the reconstitution of Cdc25A in USP29-depleted cells significantly increased the tumor size. Altogether, our results implied that USP29 promoted cell cycle progression and oncogenic transformation by regulating protein turnover of Cdc25A.

Highlights

Recent findings in the fields of cancer and cell cycle regulation have highlighted the coordination of cell proliferation and DNA replication mechanisms [1,2,3,4]
To examine the regulation of Cell division cycle 25A (Cdc25A) protein stability by ubiquitin-specific protease 29 (USP29), we monitored Cdc25A expression in human embryonic kidney 293 (HEK293) cells cultured in the presence of an increasing concentration of USP29
Ectopic expression of catalytically deficient mutant USP29 (USP29CA) was unable to stabilize the Cdc25A protein (Figure 1B), suggesting that the regulation of Cdc25A stability by USP29 was dependent on the deubiquitinating enzyme (DUB) activity of USP29

Summary

Introduction

Recent findings in the fields of cancer and cell cycle regulation have highlighted the coordination of cell proliferation and DNA replication mechanisms [1,2,3,4]. Cdc25A is a potential candidate protein contributing to progression of tumors by regulating the cancer cell cycle. The rate of Cdc25A protein turnover is controlled by the ubiquitin proteasomal pathway. Several deubiquitinating enzymes (DUBs) are involved in cell cycle regulation and cancer progression by stabilizing their target substrates [15,16,17]. Four mechanisms have been identified for DUBs: (i) ubiquitin precursor molecule processing, (ii) ubiquitin molecule recycling, (iii) polyubiquitin chain degradation, and (iv) reversal of ubiquitin conjugation. By harnessing these mechanisms, DUBs can rescue the target protein from proteasomal- and lysosomal-dependent degradations. Researchers are focusing on therapeutic intervention in DUB activity in the search for new anticancer drugs

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Results

Conclusion