Dataset Information

PGC1? Regulates Breast Tumor Growth and Metastasis by SREBP1-Mediated HKDC1 Expression.

ABSTRACT: Background: Breast cancer is a very common cancer with significant premature mortality in women. In this study, we show that HKDC1 expression in breast cancer cells is increased significantly. We aim to investigate the detailed mechanism for the regulation of HKDC1 expression and its potential contribution to tumorigenesis. Methods: Gene expression was evaluated by real time PCR, western blotting, and immunohistochemistry. The mechanism for PGC1?/SREBP1-mediated HKDC1 expression was investigated using luciferase reporter assay, chromatin immunoprecipitation, and siRNA techniques. In addition, HKDC1 was overexpressed or knocked down by lentivirus to evaluate the potential effect on in vitro cell proliferation, glucose uptake, mitochondrial function, apoptosis, and reactive oxygen species (ROS) formation. Furthermore, an in vivo xenograft tumor development study was employed to investigate the effect of HKDC1 on tumor growth and mouse survival. Results: HKDC1 is highly expressed in both breast cancer cells and clinical tumor tissues. HKDC1 expression is upregulated and co-activated by PGC1? through SREBP1 binding motif on the HKDC1 promoter. HKDC1 is located on the mitochondrial membrane and regulates the permeability transition pore opening by binding with VDAC1, subsequently modulating glucose uptake and cell proliferation. Overexpression of HKDC1 increases while knockdown of HKDC1 decreases in vitro breast cancer cell proliferation and in vivo tumor growth, metastasis, and mouse survival. Conclusions: PGC1? regulates breast cancer tumor growth and metastasis by SREBP1-mediated HKDC1 expression. This provides a novel therapeutic strategy through targeting the PGC1?/HKDC1 signaling pathway for breast cancer treatment.

SUBMITTER: Chen X

PROVIDER: S-EPMC6478765 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

PGC1β Regulates Breast Tumor Growth and Metastasis by SREBP1-Mediated HKDC1 Expression.

Chen Xiaoli X Lv Yang Y Sun Ying Y Zhang Hongyu H Xie Weiguo W Zhong Liyan L Chen Qi Q Li Min M Li Ling L Feng Jia J Yao Athena A Zhang Qi Q Huang Xiaodong X Yu Zhendong Z Yao Paul P

Frontiers in oncology 20190417

<b>Background:</b> Breast cancer is a very common cancer with significant premature mortality in women. In this study, we show that HKDC1 expression in breast cancer cells is increased significantly. We aim to investigate the detailed mechanism for the regulation of HKDC1 expression and its potential contribution to tumorigenesis. <b>Methods:</b> Gene expression was evaluated by real time PCR, western blotting, and immunohistochemistry. The mechanism for PGC1β/SREBP1-mediated HKDC1 expression wa ...[more]

PMID: 31058090

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Project description:KAP1 is overexpressed in breast cancer. To determine KAP1 regulated genes, we performed microarray analysis of gene expression in KAP1 depleted breast cancer cells MDA-MB-231LN. The transcriptional regulator TRIM28/KAP1 plays an important role in development, stem cell self-renewal, chromatin organization and the DNA damage response. KAP1 is an essential co-repressor for KRAB zinc finger proteins (KRAB-ZNFs). Though KRAB-ZNFs represent the largest family of human transcription factors, their biological functions are largely unknown. Using the conserved zinc fingers linker region (ZnFL) as antigen, we have developed a ZnFL antibody that recognizes multiple KRAB-ZNFs. We showed that KAP1 and many KRAB-ZNFs were overexpressed in human breast cancers and breast cancer cell lines. In addition, an active SUMOylated form of KAP1 was markedly increased in breast cancer cells. Furthermore, KAP1 depletion in breast cancer cell lines reduced cell proliferation and inhibited tumor growth and metastasis of tumor xenografts. Conversely, KAP1 overexpression stimulated cell proliferation and tumor growth. KAP1 knockdown led to down-regulation of genes previously linked to tumor progression and metastasis, including PTGS2/COX2, EREG, CD44, MMP1 and MMP2. Interestingly, KAP1 depletion or genomic deletion led to dramatic down-regulation of multiple KRAB-ZNF proteins due in part to their increased degradation. KAP1-dependent stabilization of KRAB-ZNFs required a direct KRAB-ZNF-KAP1 interaction. These results establish KAP1 as a positive regulator of multiple KRAB-ZNFs and an important factor in the development of breast cancer. 7 total samples were analyzed. Stable sublines of MDA-MB-231LN cells expressing control non-targeting shRNA (Scr, 3 biological replicates) and two different shRNAs against KAP1 (KAP1-3, 2 biological replicates and KAP1-4, 2 biological replicates) from doxycycline-inducible pTRIPZ vector were cultured in the presence of 0.5 ug/ml doxycycline for 7 days to induce shRNA expression. Cells were lysed and total RNA was isolated using mirVana miRNA isolation kit (Ambion) in the WVU Genomics Core Facility.

Dataset Information

PGC1? Regulates Breast Tumor Growth and Metastasis by SREBP1-Mediated HKDC1 Expression.

Publications

PGC1β Regulates Breast Tumor Growth and Metastasis by SREBP1-Mediated HKDC1 Expression.

Similar Datasets

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