Cip2a promotes cell cycle progression in triple-negative breast cancer cells by regulating the expression and nuclear export of p27Kip1
Abstract
Triple-negative breast cancer (TNBC) is very aggressive and currently has no specific therapeutic targets; as a consequence, TNBC exhibits poor clinical outcome. In this study, we showed that cancerous inhibitor of protein phosphatase 2A (Cip2a) represents a promising target in TNBC because Cip2a was highly expressed in TNBC cells and tumor tissues, and its expression showed an inverse correlation with overall survival in patients with TNBC. We found that inhibition of Cip2a in TNBC cells induced cell cycle arrest at the G2/M phase, inhibited cell proliferation and delayed tumor growth in the xenograft model. Moreover, Cip2a markedly decreased the expression and nuclear localization of p27Kip1 and this is critical for the ability of Cip2a to promote TNBC progression. Mechanistically, our studies showed that Cip2a promoted p27Kip1 phosphoration at Ser10 via inhibiting Akt-associated PP2A activity, which seems to relocalize p27Kip1 to the cytoplasm in TNBC cells. On the other hand, Cip2a also recruited c-myc to mediate the transcriptional inhibition of p27Kip1. Notably, we observed negative correlation between Cip2a and p27Kip1 expression in TNBC specimens. In addition, our data showed that Cip2a depletion could sensitize TNBC to PARP inhibition. Collectively, these data suggested that Cip2a effectively promotes TNBC cell cycle progression and tumor growth via regulation of PP2A/c-myc/p27Kip1 signaling, which could serve as a potential therapeutic target for TNBC patients.
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The therapeutic effect of inhibition of CIP2A protein expression in tumor growth has been validated by numerous studies.
“The therapeutic effect of inhibition of CIP2A protein expression in tumor growth has been recently validated by numerous studies [10,14 -18].”
From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [18]
Targeting CIP2A binding to B56 could constitute a first structure-based strategy for therapeutic inhibition of CIP2A protein stability and activity.
“As functional consequences of high CIP2A protein expression on tumorigenesis are very well established in numerous recent studies [10,14 -18], it is conceivable that targeting of CIP2A binding to B56 could constitute a first structure-based strategy for therapeutic inhibition of CIP2A protein stability and activity.”
From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [18]
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Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56
Wang, J., Okkeri, J., Pavic, K., Wang, Z., Kauko, O., Halonen, T., Sarek, G., Ojala, P. M., Rao, Z., Xu, W., et al. (2017) · The EMBO Reports · doi:10.15252/embr.201642788 · Cited by 95 · see citing works
- Authors
- Liu, H., Qiu, H., Song, Y., Liu, Y., Wang, H., Lu, M., Deng, M., Gu, Y., Yin, J., Luo, K., Zhang, Z., Jia, X., Zheng, G., & He, Z.
- Affiliations
- Guangzhou Medical University Cancer Hospital (CN)
- Sun Yat-sen University (CN)
- Venue
- Oncogene
- Published
- 2016-10-03
- Volume
- 36
- Issue
- 14
- Pages
- 1952-1964
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2529304765
- Cited by
- 19
- References
- 59
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 4 · 2018: 3 · 2017: 4
- FWCI
- 1.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- CIP2A, triple-negative breast cancer, p27, cell cycle progression, G2/M cell cycle arrest, protein phosphatase 2A, Akt, c-Myc, nuclear export, PARP inhibitor sensitivity, therapeutic target
- MeSH terms
- Adult, Aged, Aged, 80 and over, Animals, Autoantigens, Cell Division, Cell Nucleus, Female, Humans, Membrane Proteins, Mice, Nude, Middle Aged, Gene Expression Regulation, Neoplastic, Protein Transport, Active Transport, Cell Nucleus, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Cyclin-Dependent Kinase Inhibitor p27, Mice, MCF-7 Cells, Triple Negative Breast Neoplasms
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