Histone Deacetylases Activate Hepatocyte Growth Factor Signaling by Repressing MicroRNA-449 in Hepatocellular Carcinoma Cells

Buurman, R; Gürlevik, Engin; Schäffer, Vera; Eilers, Marlies; Sandbothe, Maria; Kreipe, Hans; Wilkens, Ludwig; Schlegelberger, Brigitte; Kühnel, Florian; Skawran, Britta

doi:10.1053/j.gastro.2012.05.033

Cited by 182 publications

(132 citation statements)

References 48 publications

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“…Earlier studies have shown that the PI3K/Akt and MAPK/ERK pathways are downstream targets of MET (20,25). Here, we show that BATF2 mainly blunted HGF-induced activation of Akt, but not ERK.…”

Section: Discussionsupporting

confidence: 48%

“…S1). Moreover, several studies have shown that activation of HGF/MET signaling promotes the progression of many tumors via PI3K/Akt and/or MAPK/ERK (20,25). Our Western blot data revealed that BATF2 overexpression significantly attenuated the levels of phosphorylated Akt (p-Akt) in both LoVo and SW620 cells but only slightly decreased phosphorylated ERK 1/2 (p-ERK 1/2) in LoVo cells (Fig.…”

Section: Batf2 Downregulates Met Expression By Inhibiting Transcriptimentioning

confidence: 55%

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BATF2 Deficiency Promotes Progression in Human Colorectal Cancer via Activation of HGF/MET Signaling: A Potential Rationale for Combining MET Inhibitors with IFNs

Liu

Wei

et al. 2015

Clinical Cancer Research

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Purpose: BATF2, a novel IFN-stimulated gene, inhibits tumor cell proliferation, invasion, and migration. The objectives of this study were to determine how BATF2 expression is associated with colorectal cancer progression and patient outcome, to investigate how BATF2 overexpression inhibits hepatocyte growth factor (HGF)/MET signaling, and to elucidate the rationale for combining MET inhibitors with IFN.Experimental Design: BATF2 expression in colorectal cancer tissues was determined and correlated with colorectal cancer patient prognosis. Cultured colorectal cancer cells were used to investigate the effects of BATF2 overexpression on the malignant phenotype of colorectal cancer cells and HGF/MET signaling. Tumor xenograft models were used to validate the effects of BATF2 on colorectal cancer xenograft growth and assess the efficacy of the combination of MET inhibitors with IFNs in colorectal cancer. Results:In colorectal cancer tissues, BATF2 was found to be significantly downregulated, and its expression negatively correlated with MET expression. Decreased BATF2 expression was associated with progression and shorter patient survival in colorectal cancer. BATF2 overexpression promoted apoptosis and inhibited proliferation, migration, and invasion in colorectal cancer cells, as well as dramatically blunted tumor xenograft growth. In addition, MET inhibitors in combination with IFNb produced synergistic cytotoxicity both in vitro and in vivo.Conclusions: Together, these novel findings suggest that BATF2, a tumor suppressor gene, is a potent negative regulator of HGF/MET signaling in colorectal cancer and may serve as a prognostic tumor marker. Furthermore, these results provide a rationale for combining MET inhibitors with IFNs in preclinical trials.

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Section: Discussionsupporting

confidence: 48%

Section: Batf2 Downregulates Met Expression By Inhibiting Transcriptimentioning

confidence: 55%

BATF2 Deficiency Promotes Progression in Human Colorectal Cancer via Activation of HGF/MET Signaling: A Potential Rationale for Combining MET Inhibitors with IFNs

Liu

Wei

et al. 2015

Clinical Cancer Research

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“…92,93 miR200a was shown to target HDAC4, while miR-449a was found to modulate HDAC1 and subsequently induce cell cycle arrest, apoptosis, and a senescent phenotype in prostate and hepatocellular cancers and myeloid leukemia cells. [94][95][96] Introduction of miR-148a and miR-34b/c in cancer cells was shown to inhibit their cell motility, reduce tumor growth, and impair metastasis formation in xenograft models, and led to a downregulation of microRNA-dependent protein targets, such as c-MYB, c-MYC, E2F3, CDK6, HDAC, and TGIF2. 97 Once it was widely demonstrated that an aberrant microRNAome is a hallmark in cancer, accumulating evidence showed that the microRNA expression is affected by the same epigenetic mechanisms as mRNA transcription.…”

Section: Discussionmentioning

confidence: 99%

Phospho-ΔNp63α/microRNA network modulates epigenetic regulatory enzymes in squamous cell carcinomas

Ratovitski

2014

Cell Cycle

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“…miR-34a is widely suppressed in cancer cells, and the highly enriched miR-34a-responsive genes regulate cell proliferation, apoptosis and angiogenesis (10). Therefore, miR-34a has become a promising target for developing novel (11)(12)(13). In addition, the expression of miR-34a is positively regulated by p53 (14) and HDAC1 suppresses p53 activity via deacetylation (15).…”

Section: Introductionmentioning

confidence: 99%

Depletion of histone deacetylase 1 inhibits metastatic abilities of gastric cancer cells by regulating the miR-34a/CD44 pathway

et al. 2015

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Abstract. Overexpression of histone deacetylases (HDACs) is associated with higher metastatic rates and a poor prognosis in gastric cancer. However, the underlying mechanisms involved remain unclear. The present study aimed to investigate the molecular pathways that are involved in HDAC1-mediated metastatic activities in gastric cancer cells. First we used a microRNA (miRNA or miR) microarray to screen potential miRNAs whose expression can be altered by HDAC1 depletion. Of these miRNAs, miR-34a is important as it is often inactivated in cancer cells and acts as a tumor suppressor for various types of cancer. The reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results confirmed that miR-34a was upregulated by HDAC1 knockdown. Cells depleted of HDAC1 had lower abilities to migrate, invade and adhere, which were restored by a miR-34a antagomiR. Depletion of HDAC1 also resulted in impaired microfilaments and microtubules, while co-transfection of the miR-34a antagomiR attenuated these changes in the cellular cytoskeleton. The HDAC1/miR-34a axis regulated the expression and activation of CD44 and its downstream factors including Bcl-2, Ras homolog family member A (RhoA), LIM domain kinase 1 (LIMK-1) and matrix metalloproteinase (MMP)-2. The latter three proteins were responsible for the organization of tubulin and actin cytoskeleton and the formation of cellular pseudopodia. In conclusion, results of the present study indicated that HDAC1 depletion inhibits the metastatic abilities of gastric cancer cells by regulating the miRNA-34a/CD44 pathway, which may be a potential target for the treatment of gastric cancer. IntroductionGastric cancer remains the fourth most common malignancy and the second leading cause of cancer-related mortality worldwide, although its incidence is gradually on the decrease in most parts of the world (1). The currently available chemotherapeutic agents have only limited benefits for most gastric cancer patients. Therefore, identification of novel targets and an understanding of their molecular mechanisms is crucial for the treatment of gastric cancer patients.Histone deacetylases (HDACs) are a class of enzymes that remove the acetyl groups from core histones, as well as non-histone proteins, such as p53 (2). By modifying the status of deacetylation, HDACs induce transcriptional repression through chromatin condensation and alteration of protein activity (3). Among the 18 HDAC family members, HDAC1 accounts for more than half of cellular HDAC activity, and cannot be compensated by other HDACs (4). HDAC1 acts at all levels of gene expression including microRNA (miRNA or miR) regulation (5). Overexpression of HDAC1 is significantly associated with higher lymphatic metastases and decreased 3-year survival rates in gastric cancer patients (6). Many HDAC inhibitors have been developed, several of which have shown promise and are under investigation in clinical trials (3,7). However, the underlying mechanisms for the anti-metastatic activities of HDAC inhibitors, particularly...

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Histone Deacetylases Activate Hepatocyte Growth Factor Signaling by Repressing MicroRNA-449 in Hepatocellular Carcinoma Cells

Cited by 182 publications

References 48 publications

BATF2 Deficiency Promotes Progression in Human Colorectal Cancer via Activation of HGF/MET Signaling: A Potential Rationale for Combining MET Inhibitors with IFNs

BATF2 Deficiency Promotes Progression in Human Colorectal Cancer via Activation of HGF/MET Signaling: A Potential Rationale for Combining MET Inhibitors with IFNs

Phospho-ΔNp63α/microRNA network modulates epigenetic regulatory enzymes in squamous cell carcinomas

Depletion of histone deacetylase 1 inhibits metastatic abilities of gastric cancer cells by regulating the miR-34a/CD44 pathway

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