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Downregulation of ubiquitin-specific peptidase 39 suppresses the proliferation and induces the apoptosis of human colorectal cancer cells.

ABSTRACT: Ubiquitin-specific peptidase 39 (USP39) has been reported to participate in the mitotic spindle checkpoint and the process of cytokinesis. and has been identified as a therapeutic target for various types of cancer. However, the effect of USP39 in colorectal cancer (CRC) has not been investigated. To explore the functional role of USP39 in CRC cell growth, lentivirus-mediated RNA interference was applied to inhibit USP39 expression in SW1116 and HCT116 cells. The relative USP39 mRNA and protein expression levels were significantly reduced in the USP39 knockdown cells, as verified by reverse transcription-quantitative polymerase chain reaction and western blot analysis. USP39 knockdown significantly reduced the proliferation and colony formation abilities of CRC cells, and induced apoptosis and cell cycle arrest in the G2/M phases, as determined by an MTT assay, a colony formation assay and flow cytometry analysis. Furthermore, western blot analysis demonstrated that USP39 knockdown may have induced apoptosis through the upregulation of p53, p-p53, PARP and caspase-3 expression in SW1116 cells. In conclusion, USP39 may be a novel biological marker for targeted therapy against CRC, and requires further investigation.

SUBMITTER: Xing Z

PROVIDER: S-EPMC5844003 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Downregulation of ubiquitin-specific peptidase 39 suppresses the proliferation and induces the apoptosis of human colorectal cancer cells.

Xing Zhiyuan Z Sun Fengbo F He Wang W Wang Zhiwei Z Song Xiuqi X Zhang Fengjuan F

Oncology letters 20180215 4

Ubiquitin-specific peptidase 39 (USP39) has been reported to participate in the mitotic spindle checkpoint and the process of cytokinesis. and has been identified as a therapeutic target for various types of cancer. However, the effect of USP39 in colorectal cancer (CRC) has not been investigated. To explore the functional role of USP39 in CRC cell growth, lentivirus-mediated RNA interference was applied to inhibit USP39 expression in SW1116 and HCT116 cells. The relative USP39 mRNA and protein ...[more]

PMID: 29556295

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Project description:BACKGROUND:Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide, and deciphering underlying molecular mechanism is essential. The loss of monoubiquitinated histone H2B (H2Bub1) was correlated with poor prognosis of CRC patients and, accordingly, H2Bub1 was suggested as a tumor-suppressive mark. Surprisingly, our previous work revealed that the H2B ubiquitin ligase RING finger protein 40 (RNF40) might exert tumor-promoting functions. Here, we investigated the effect of RNF40 loss on tumorigenic features of CRC cells and their survival in vitro. METHODS:We evaluated the effects of RNF40 depletion in several human CRC cell lines in vitro. To evaluate cell cycle progression, cells were stained with propidium iodide and analyzed by flow cytometry. In addition, to assess apoptosis rates, caspase 3/7 activity was assessed in a Celigo® S-based measurement and, additionally, an Annexin V assay was performed. Genomic occupancy of H2Bub1, H3K79me3, and H3K27ac was determined by chromatin immunoprecipitation. Transcriptome-wide effects of RNF40 loss were evaluated based on mRNA-seq results, qRT-PCR, and Western blot. To rescue apoptosis-related effects, cells were treated with Z-VAD-FMK. RESULTS:Human CRC cell lines displayed decreased cell numbers in vitro after RNF40 depletion. While the differences in confluence were not mediated by changes in cell cycle progression, we discovered highly increased apoptosis rates after RNF40 knockdown due to elevated caspase 3/7 activity. This effect can be explained by reduced mRNA levels of anti-apoptotic and upregulation of pro-apoptotic BCL2 family members. Moreover, the direct occupancy of the RNF40-mediated H2B monoubiquitination was observed in the transcribed region of anti-apoptotic genes. Caspase inhibition by Z-VAD-FMK treatment rescued apoptosis in RNF40-depleted cells. However, knockdown cells still displayed decreased tumorigenic features despite the absence of apoptosis. CONCLUSIONS:Our findings reveal that RNF40 is essential for maintaining tumorigenic features of CRC cells in vitro by controlling the expression of genes encoding central apoptotic regulators.

Dataset Information

Downregulation of ubiquitin-specific peptidase 39 suppresses the proliferation and induces the apoptosis of human colorectal cancer cells.

Publications

Downregulation of ubiquitin-specific peptidase 39 suppresses the proliferation and induces the apoptosis of human colorectal cancer cells.

Similar Datasets

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