Ubiquitin-Specific Protease 29 Regulates Cdc25A-Mediated Tumorigenesis

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.

Phosphorylation of USP29 by CDK1 Governs TWIST1 Stability and Oncogenic Functions

“…[ 17 ] In a cervical cancer study, the overexpression of USP29 enables the stabilization of the cell division cycle 25A (Cdc25A) and enhances the oncogenic potential of HeLa cells. [ 18 ] In addition, USP29 was reported to promote gastric cancer cell migration by cooperating with phosphatase SCP1 to stabilize Snail protein. [ 20 ] However, we found that the knockdown of USP29 significantly decreased the protein level of TWIST1, but only slightly affected the protein level of Snail1 in MDA‐MB‐231 and BT549 cells (Figure S2D, Supporting Information).…”

Circadian Rhythm Dysregulation and Leukemia Development: The Role of Clock Genes as Promising Biomarkers

“…Song et al [ 95 ] showed that NPAS2 was up-regulated in AML patients compared to controls, and that NPAS2 knockdown in AML cells led to cell cycle arrest at the G1 and G2 phases, as well as apoptosis in leukemic cells, which may suggest the participation of this gene in the development of leukemia, demonstrating its possible role as biomarker of the disease. Moreover, the study also investigated the role of NPAS2 in the cell division cycle 25A (CDC25A), a dual-specificity phosphatase that participates in the progression of the G1 to the S phase together with CDKs, and which may have its expression regulated by transcription factors [ 139 , 140 , 141 , 142 ]. High levels of CDC25A have already been reported in tumorigenic cells [ 143 , 144 , 145 , 146 , 147 ].…”

The emerging role of USP29 in cancer and other diseases

“…Mechanistically, USP29 promoted Cdc25A-dependent cell cycle progression by regulating the protein stability of Cdc25A. 29 USP29 was highly upregulated in colon cancer tissues and promoted cancer cell proliferation; although the detailed mechanism was unclear, USP29 depletion was reported to delay cell cycle progression. 17 Recently, another study for colon cancer presented the accordant result that USP29 facilitates the malignant proliferation of cancer cells by upregulating the KIAA1429/SOX8 axis both in vitro and in vivo.…”

“…In cervical cancer HeLa cells, depletion of USP29 induced an impaired G1‐S phage transition and an accumulation of cells at G0/G1 phase, and this was rescued by reconstituted cell division cycle 25A (Cdc25A), which is a regulator of cell cycle progression. Mechanistically, USP29 promoted Cdc25A‐dependent cell cycle progression by regulating the protein stability of Cdc25A 29 . USP29 was highly upregulated in colon cancer tissues and promoted cancer cell proliferation; although the detailed mechanism was unclear, USP29 depletion was reported to delay cell cycle progression 17 .…”