Targeting<i>CDKN3</i>in cervical cancer

Berumen, Jaime; Espinosa, Ana; Medina, Ingrid

doi:10.1517/14728222.2014.941808

Cited by 26 publications

(22 citation statements)

References 60 publications

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“…CDK6 expression was downregulated in MAFB knockdown SW1116 cells, while CDKN3, CUL1 and CUL3 were upregulated (Figure 3A). This was consistent with the findings of other G1 phase arrest studies [21–24]. We also found that CCNB1 and CCND1 were downregulated (Supplementary Figure S3), which was in agreement with previous work [15].…”

Section: Resultssupporting

confidence: 94%

SUMOylated MAFB promotes colorectal cancer tumorigenesis

et al. 2016

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The transcription factor, v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB), promotes tumorigenesis in some cancers. In this study, we found that MAFB levels were increased in clinical colorectal cancer (CRC) samples, and higher expression correlated with more advanced TNM stage. We identified MAFB amplifications in a majority of tumor types in an assessment of The Cancer Genome Atlas database. Altered MAFB levels due to gene amplification, deletion, mutation, or transcription upregulation occurred in 9% of CRC cases within the database. shRNA knockdown experiments demonstrated that MAFB deficiency blocked CRC cell proliferation by arresting the cell cycle at G0/G1 phase in vitro. We found that MAFB could be SUMOylated by SUMO1 at lysine 32, and this modification was critical for cell cycle regulation by MAFB in CRC cells. SUMOylated MAFB directly regulated cyclin-dependent kinase 6 transcription by binding to its promoter. MAFB knockdown CRC cell xenograft tumors in mice grew more slowly than controls, and wild-type MAFB-overexpressing tumors grew more quickly than tumors overexpressing MAFB mutated at lysine 32. These data suggest that SUMOylated MAFB promotes CRC tumorigenesis through cell cycle regulation. MAFB and its SUMOylation process may serve as novel therapeutic targets for CRC treatment.

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Section: Resultssupporting

confidence: 94%

SUMOylated MAFB promotes colorectal cancer tumorigenesis

et al. 2016

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“…The association between CDKN3 and tumorigenesis has previously been reported in several studies ( 4 – 6 ). However, the molecular mechanisms underlying the effects of CDKN3 on cell cycle arrest, apoptosis and cell migration remain to be determined.…”

Section: Introductionmentioning

confidence: 52%

“…It was initially identified as a CDK inhibitor, which interacts with, and dephosphorylates CDK2, thus preventing its activation ( 4 ). Aberrant expression of CDKN3, including deletion, mutation, or overexpression has been reported in numerous types of cancer ( 4 – 6 ). However, the exact role of CDKN3 in the progression of breast cancer remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Silencing cyclin-dependent kinase inhibitor 3 inhibits the migration of breast cancer cell lines

Deng

Wang

Chen

et al. 2016

Molecular Medicine Reports

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Cyclin-dependent kinase inhibitor 3 (CDKN3) belongs to the dual-specificity protein phosphatase family, which is hypothesized to regulate cell cycle progression in tumor cells. However, whether CDKN3 is a potential therapeutic target for breast cancer remains to be elucidated. The present in vitro study aimed to investigate the potential roles of CDKN3 in breast cancer. Breast cancer cell lines were used to detect CDKN3 expression, and CDKN3 expression was silenced to investigate its role in cell apoptosis, cell cycle arrest and migration. The underlying mechanisms were screened by detecting proliferating cell nuclear antigen (PCNA), Ras homolog gene family, member A (RhoA), vimentin, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) expression. CDKN3 was highly expressed in MCF-7 and BT474 cell lines. The silencing of CDKN3 in MCF-7 and BT474 cell lines promoted cell apoptosis, induced G1 phase cell cycle arrest and inhibited cell migration. The expression levels of PCNA, RhoA, vimentin and Bcl-2 were downregulated following CDKN3 silencing. Conversely, Bax expression was increased, as compared with the vehicle control. These results suggest that CDKN3 acts as an oncogene during breast cancer progression. The in vitro silencing of CDKN3 promoted apoptosis, induced G1 phase cell cycle arrest and inhibited cell migration. Possible mechanisms are associated with the regulation of PCNA, Bcl-2, vimentin, RhoA and Bax expression. CDKN3 may therefore be considered a potential target for the treatment of breast cancer.

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“…In agreement with our data, upregulation of CDKN3 gene, together with other genes, has been associated with decreased survival of patients with lung cancer [ 40 ] and astrocytoma [ 43 ]. Furthermore, CDKN3 inhibition in many cell lines decreases cell proliferation, suggesting that this gene acts as an oncogene [ 47 ]. However, overexpression of CDKN3 has been associated with the inhibition of cell proliferation in glioblastoma [ 42 , 48 ] and leukemic [ 49 ] cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, CDKN3 protein, a dual-specificity protein phosphatase of the Cdc14 phosphatase group, also appears to be essential in the regulation of mitosis exit. It interacts with CDK1 (CDC2) and inhibits its activity, and dephosphorylates many of the proteins phosphorylated by CDK1 [ 47 , 48 ]. CDKN3 and other Cdc14 phosphatases appear to be essential for antagonizing Cdk activity in late mitosis, allowing cells to exit mitosis and enter cytokinesis.…”

Section: Discussionmentioning

confidence: 99%

CDKN3 mRNA as a Biomarker for Survival and Therapeutic Target in Cervical Cancer

et al. 2015

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The cyclin-dependent kinase inhibitor 3 (CDKN3) gene, involved in mitosis, is upregulated in cervical cancer (CC). We investigated CDKN3 mRNA as a survival biomarker and potential therapeutic target for CC. CDKN3 mRNA was measured in 134 CC and 25 controls by quantitative PCR. A 5-year survival study was conducted in 121 of these CC patients. Furthermore, CDKN3-specific siRNAs were used to investigate whether CDKN3 is involved in proliferation, migration, and invasion in CC-derived cell lines (SiHa, CaSki, HeLa). CDKN3 mRNA was on average 6.4-fold higher in tumors than in controls (p = 8 x 10−6, Mann-Whitney). A total of 68.2% of CC patients over expressing CDKN3 gene (fold change ≥ 17) died within two years of diagnosis, independent of the clinical stage and HPV type (Hazard Ratio = 5.0, 95% CI: 2.5–10, p = 3.3 x 10−6, Cox proportional-hazards regression). In contrast, only 19.2% of the patients with lower CDKN3 expression died in the same period. In vitro inactivation of CDKN3 decreased cell proliferation on average 67%, although it had no effect on cell migration and invasion. CDKN3 mRNA may be a good survival biomarker and potential therapeutic target in CC.

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TargetingCDKN3in cervical cancer

Abstract: CDKN3 might be useful not only as marker for survival and selection of CC patients for additional chemotherapy or specific target cancer therapy, but also as a potential target to develop specific small drugs to combat CC.

Cited by 26 publications

References 60 publications

SUMOylated MAFB promotes colorectal cancer tumorigenesis

SUMOylated MAFB promotes colorectal cancer tumorigenesis

Silencing cyclin-dependent kinase inhibitor 3 inhibits the migration of breast cancer cell lines

CDKN3 mRNA as a Biomarker for Survival and Therapeutic Target in Cervical Cancer

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