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Transcriptional positive cofactor 4 promotes breast cancer proliferation and metastasis through c-Myc mediated Warburg effect.

ABSTRACT: BACKGROUND:The human positive cofactor 4 (PC4) is initially identified as a transcriptional cofactor and has an important role in embryonic development and malignant transformation. However, the clinical significance and the molecular mechanisms of PC4 in breast cancer development and progression are still unknown. METHODS:We investigated PC4 expression in 114 cases of primary breast cancer and matched normal breast tissue specimens, and studied the impact of PC4 expression as well as the molecular mechanisms of this altered expression on breast cancer growth and metastasis both in vitro and in vivo. RESULTS:PC4 was significantly upregulated in breast cancer and high PC4 expression was positively correlated with metastasis and poor prognosis of patients. Gene set enrichment analysis (GSEA) demonstrated that the gene sets of cell proliferation and Epithelial-Mesenchymal Transition (EMT) were positively correlated with elevated PC4 expression. Consistently, loss of PC4 markedly inhibited the growth and metastasis of breast cancer both in vitro and in vivo. Mechanistically, PC4 exerted its oncogenic functions by directly binding to c-Myc promoters and inducing Warburg effect. CONCLUSIONS:Our study reveals for the first time that PC4 promotes breast cancer progression by directly regulating c-Myc transcription to promote Warburg effect, implying a novel therapeutic target for breast cancer.

SUBMITTER: Luo P

PROVIDER: S-EPMC6469038 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Transcriptional positive cofactor 4 promotes breast cancer proliferation and metastasis through c-Myc mediated Warburg effect.

Luo Peng P Zhang Chi C Liao Fengying F Chen Long L Liu Zhenyu Z Long Lei L Jiang Zhongyong Z Wang Yawei Y Wang Ziwen Z Liu Zujuan Z Miao Hongming H Shi Chunmeng C

Cell communication and signaling : CCS 20190416 1

<h4>Background</h4>The human positive cofactor 4 (PC4) is initially identified as a transcriptional cofactor and has an important role in embryonic development and malignant transformation. However, the clinical significance and the molecular mechanisms of PC4 in breast cancer development and progression are still unknown.<h4>Methods</h4>We investigated PC4 expression in 114 cases of primary breast cancer and matched normal breast tissue specimens, and studied the impact of PC4 expression as wel ...[more]

PMID: 30992017

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Project description:Background: DC-STAMP domain containing 1-antisense 1 (DCST1-AS1) is a long noncoding RNA (lncRNA) that is up-regulated in triple-negative breast cancer (TNBC) tissues. Here, we attempt to investigate the oncogenic property of DCST1-AS1. Methods: LncRNA microarrays were used to detect differentially expressed lncRNA in cancerous tissues. Fluorescence in situ hybridization assay was used to detect the distribution of DCST1-AS1 in BT-549 and MDA-MB-231 cells. Lentiviral systems, inhibitors, siRNA and overexpression plasmids were used for gain- and loss-of-function experiments. Colony formation assay, wound healing assay, CCK8 assay, transwell assay, and flow cytometry assay were used to study the function of DCST1-AS1. Luciferase assay was used to verify the binding of MYC to the promoter region and the binding of miR-873-5p to DCST1-AS1. RNA immunoprecipitation assay was used to verify that argonaute 2 binds to both miR-873-5p and DCST1-AS1. Western blotting was used to measure changes in protein expression. Results: Consistent with the microarray results, we found that DCST1-AS1 was up-regulated in both TNBC tissue samples and cell lines. DCST1-AS1 was positively correlated with distant metastasis and histopathological grades. DCST1-AS1 is distributed in both nucleus and cytoplasm. Knockdown of DCST1-AS1 inhibits TNBC cell proliferation and metastasis, while overexpression of DCST1-AS1 promotes TNBC cell proliferation and metastasis. We confirmed that DCST1-AS1 expression in TNBC cells is regulated by MYC. Furthermore, we found that DCST1-AS1 is negatively correlated with miR-873-5p in TNBC tissues and is a direct target gene of miR-873-5p. Argonaute 2 is involved in the binding of DCST1-AS1 and miR-873-5p and promotes the degradation of DCST1-AS1. The interaction of DCST1-AS1 with miR-873-5p ultimately up-regulated the expression of insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), MYC, CD44 and lymphoid enhancer binding factor 1 (LEF1). Conclusions: DCST1-AS1 is activated by MYC and is degraded by binding to miR-873-5p, thereby upregulating the expression of miR-873-5p downstream proteins IGF2BP1, MYC, LEF1 and CD44. MYC, DCST1-AS1 and miR-873-5p form a positive regulatory loop to promote TNBC cell proliferation and metastasis.

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Transcriptional positive cofactor 4 promotes breast cancer proliferation and metastasis through c-Myc mediated Warburg effect.

Publications

Transcriptional positive cofactor 4 promotes breast cancer proliferation and metastasis through c-Myc mediated Warburg effect.

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