PRR11 and SKA2 gene pair is overexpressed and regulated by p53 in breast cancer
1
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Our previous study found that two novel cancer-related genes, PRR11 and SKA2, constituted a classic gene pair that was regulated by p53 and NF-Y in lung cancer. However, their role and regulatory mechanism in breast cancer remain elusive. In this study, we found that the expression levels of PRR11 and SKA2 were upregulated and have a negative prognotic value in breast cancer. Loss-of-function experiments showed that RNAi-mediated knockdown of PRR11 and/or SKA2 inhibited proliferation, migration, and invasion of breast cancer cells. Mechanistic experiments revealed that knockdown of PRR11 and/or SKA2 caused dysregulation of several downstream genes, including CDK6, TPM3, and USP12, etc. Luciferase reporter assays demonstrated that wild type p53 significantly repressed the PRR11-SKA2 bidirectional promoter activity, but not NF-Y. Interestingly, NF-Y was only essential for and correlated with the expression of PRR11, but not SKA2. Consistently, adriamycin-induced (ADR) activation of endogenous p53 also caused significant repression of the PRR11 and SKA2 gene pair expression. Notably, breast cancer patients with lower expression levels of either PRR11 or SKA2, along with wild type p53, exhibited better disease-free survival compared to others with p53 mutations and/or higher expression levels of either PRR11 or SKA2. Collectively, our study indicates that the PRR11 and SKA2 transcription unit might be an oncogenic contributor and might serve as a novel diagnostic and therapeutic target in breast cancer.
Abstract
Our previous study found that two novel cancer-related genes, PRR11 and SKA2, constituted a classic gene pair that was regulated by p53 and NF-Y in lung cancer. However, their role and regulatory mechanism in breast cancer remain elusive. In this study, we found that the expression levels of PRR11 and SKA2 were upregulated and have a negative prognotic value in breast cancer. Loss-of-function experiments showed that RNAi-mediated knockdown of PRR11 and/or SKA2 inhibited proliferation, migration, and invasion of breast cancer cells. Mechanistic experiments revealed that knockdown of PRR11 and/or SKA2 caused dysregulation of several downstream genes, including CDK6, TPM3, and USP12, etc. Luciferase reporter assays demonstrated that wild type p53 significantly repressed the PRR11-SKA2 bidirectional promoter activity, but not NF-Y. Interestingly, NF-Y was only essential for and correlated with the expression of PRR11, but not SKA2. Consistently, adriamycin-induced (ADR) activation of endogenous p53 also caused significant repression of the PRR11 and SKA2 gene pair expression. Notably, breast cancer patients with lower expression levels of either PRR11 or SKA2, along with wild type p53, exhibited better disease-free survival compared to others with p53 mutations and/or higher expression levels of either PRR11 or SKA2. Collectively, our study indicates that the PRR11 and SKA2 transcription unit might be an oncogenic contributor and might serve as a novel diagnostic and therapeutic target in breast cancer.
참고문헌 (28)
- Siegel RL, "Cancer statistics, 2018 : Cancer Statistics, 2018", CA Cancer J Clin, 68, pp.7~30 (2018)
- Chen W, "Cancer statistics in China, 2015 : Cancer Statistics in China, 2015", CA Cancer J Clin, 66, pp.115~132 (2016)
- Trinklein ND, "An Abundance of Bidirectional Promoters in the Human Genome", Genome Res, 14, pp.62~66 (2003)
- Ji Y, "PRR11 is a novel gene implicated in cell cycle progression and lung cancer", Int J Biochem Cell Biol, 45, pp.645~656 (2013)
- Song Z, "PRR11 Is a Prognostic Marker and Potential Oncogene in Patients with Gastric Cancer", PLoS One, 10, pp.e0128943~ (2015)
- Chen Y, "The prognostic potential and oncogenic effects of PRR11 expression in hilar cholangiocarcinoma", Oncotarget, 6, pp.20419~20433 (2015)
- Zhang C, "PRR11 regulates late-S to G2", M phase progression and induces premature chromatin condensation(PCC), 2015, pp.458, 501~508
- Chan YW, "Aurora B controls kinetochore-microtubule attachments by inhibiting Ska complex-KMN network interaction", J Cell Biol, 196, pp.563~571 (2012)
- Guimaraes GJ, "Connecting with Ska, a key complex at the kinetochore-microtubule interface", EMBO J, 28, pp.1375~1377 (2009)
- Zhang Q, "Ska3 Phosphorylated by Cdk1 Binds Ndc80 and Recruits Ska to Kinetochores to Promote Mitotic Progression", Curr Biol, 27, pp.1477.e4~1484.e4 (2017)[DOI]
- Jeyaprakash AA, "Structural and functional organization of the Ska complex, a key component of the kinetochore-microtubule interface", Mol Cell, 46, pp.274~286 (2012)
- Welburn JPI, "The human kinetochore Ska1 complex facilitates microtubule depolymerization-coupled motility", Dev Cell, 16, pp.374~385 (2009)
- Gaitanos TN, "Stable kinetochore-microtubule interactions depend on the Ska complex and its new component Ska3", C13Orf3, 2009, pp.28, 1442~1452
- Hanisch A, "Timely anaphase onset requires a novel spindle and kinetochore complex comprising Ska1 and Ska2", EMBO J, 25, pp.5504~5515 (2006)
- Rice L, "Identification and functional analysis of SKA2 interaction with the glucocorticoid receptor", J Endocrinol, 198, pp.499~509 (2008)
- Wang Y, "The gene pair PRR11 and SKA2 shares a NF-Y-regulated bidirectional promoter and contributes to lung cancer development", Biochim Biophys Acta BBA-Gene Regul Mech, 1849, pp.1133~1144 (2015)
- Wang Y, "The PRR11-SKA2bidirectional transcription unit is negatively regulated by p53 through NF-Y in lung cancer cells", Int J Mol Sci, 18, pp.534~ (2017)
- Zhang L, "Silencing of PRR11 suppresses cell proliferation and induces autophagy in NSCLC cells", Genes Dis, 5, pp.158~166 (2018)
- Chaudhary S, "Overexpression of caspase 7 is ERalpha dependent to affect proliferation and cell growth in breast cancer cells by targeting p21(Cip)", Oncogenesis, 5, pp.e219~ (2016)
- Murphy CG, "The Role of CDK4", 6inhibition in breast cancer, 2015, pp.20, 483~490
- Wang L, "P16 promotes the growth and mobility potential of breast cancer both in vitro and in vivo : the key role of the activation of IL-6", JAK2, Mol Cell Biochem, pp.2018, 446[DOI]
- Selander KS, "Inhibition of gp130 signaling in breast cancer blocks constitutive activation of Stat3 and inhibits in vivo malignancy", Cancer Res, 64, pp.6924~6933 (2004)
- Niki T, "MSSP promotes ras", myc cooperative cell transforming activity by binding to c-Myc, 2000, pp.5, 127~141
- Lange AM, "Inhibiting TRK Proteins in clinical cancer therapy", Cancers, 10, pp.105~ (2018)
- Lehmann BD, "Targeting mutant p53 in human tumors", J Clin Oncol Off J Am Soc Clin Oncol, 30, pp.3648~3650 (2012)
- Nguyen D, "Reviving the guardian of the genome : Small molecule activators of p53", Pharmacol Ther, 178, pp.92~108 (2017)
- Miller L, "An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival", Proc Natl Acad Sci U S A, 102, pp.13550~13555 (2005)
- Gyorffy B, "An online survival analysis tool to rapidly assess the effect of 22, 277genes on breast cancer prognosis using microarray data of 1, 809 patients", Breast Cancer Res Treat, 123, pp.725~731 (2010)