Cip2a promotes cell cycle progression in triple-negative breast cancer cells by regulating the expression and nuclear export of p27Kip1.
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.
Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
H
H
Liu
Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
H
H
Qiu
Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
Y
Y
Song
Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Institute of Microbiology, Guangzhou, China.
Y
Y
Liu
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
H
H
Wang
Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
M
M
Lu
Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
M
M
Deng
Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
Y
Y
Gu
Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
J
J
Yin
Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
K
K
Luo
Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
Z
Z
Zhang
Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
X
X
Jia
Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
G
G
Zheng
Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
Z
Z
He
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001324:Autoantigens / Q000502:physiology*; D002455:Cell Division / Q000235:genetics*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D021381:Protein Transport / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*
D001324:Autoantigens; C436291:CDKN1B protein, human; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27
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