MicroRNA-34c Inversely Couples the Biological Functions of the Runt-related Transcription Factor RUNX2 and the Tumor Suppressor p53 in Osteosarcoma

Deen, Margaretha van der; Taipaleenmäki, Hanna; Zhang, Ying; Teplyuk, Nadiya M.; Gupta, Arobinda; Cinghu, Senthilkumar; Shogren, Kristen L.; Maran, Avudaiappan; Yaszemski, Michael J.; Ling, Ling; Cool, Simon M.; Leong, David Tai; Dierkes, Christian; Zustin, Jozef; Salto-Tellez, Manuel; Ito, Yoshiaki; Bae, Suk‐Chul; Zieleńska, Maria; Squire, Jeremy A.; Lian, Jane B.; Stein, Janet L.; Zambetti, Gerard P.; Jones, Stephen N.; Galindo, Mario; Hesse, Eric; Wijnen, André J. van

doi:10.1074/jbc.m112.445890

Cited by 93 publications

(68 citation statements)

References 45 publications

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“…This observation led us to the finding that BET inhibition also resulted in the downregulation of RUNX2 gene expression in osteosarcoma cells. This finding is of clinical relevance, given the emerging role of RUNX2 as a potential oncogene in osteosarcoma [12][13][14][15][16] . In addition, we found that RUNX2 gene expression, as well as that of MYC and BRD4, was higher relative to MSCs in the majority of our human osteosarcoma patient samples suggesting an addiction or at least a dependence to those oncogenes.…”

Section: Discussionmentioning

confidence: 97%

“…Moreover, MYC overexpression in a Ink4/Arf( À / À ) context was not only sufficient to transform bone marrow stromal cells but also led to osteosarcoma development 11 . In addition, RUNX2, a key transcription factor in OB differentiation, appears to be a potential oncogenic driver in osteosarcoma, depending on its expression level and cellular context [12][13][14][15] . Indeed, short interfering RNA (siRNA) knockdown of RUNX2 in U2OS osteosarcoma cells was shown to inhibit cell growth, while overexpression of RUNX2 in T-cell lymphoma synergized with MYC to promote survival and proliferation of cancer cells 13,16 .…”

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confidence: 99%

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Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle

et al. 2014

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The vicious cycle established between bone-associated tumours and bone resorption is the central problem with therapeutic strategies against primary bone tumours and bone metastasis. Here we report data to support inhibition of BET bromodomain proteins as a promising therapeutic strategy that target simultaneously the three partners of the vicious cycle. Treatment with JQ1, a BET bromodomain inhibitor, reduces cell viability of osteosarcoma cells and inhibits osteoblastic differentiation both in vitro and in vivo. These effects are associated with transcriptional silencing of MYC and RUNX2, resulting from the depletion of BRD4 from their respective loci. Moreover, JQ1 also inhibits osteoclast differentiation by interfering with BRD4-dependent RANKL activation of NFATC1 transcription. Collectively, our data indicate that JQ1 is a potent inhibitor of osteoblast and osteoclast differentiation as well as bone tumour development.

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle

et al. 2014

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“…14 It can inhibit the development of various cancers including osteosarcoma, lung cancer, uveal melanoma, prostate cancer, laryngeal carcinoma, breast cancer, and gastric cancer. [15][16][17][18][19][20][21] Previous studies show that sperm-borne miR-34c is important for the first cleavage division by Bcl -2. 22 It also modulates male germ cell development.…”

Section: Introductionmentioning

confidence: 99%

miRNA-34c inhibits myoblasts proliferation by targeting YY1

Wang

Liu

et al. 2017

Cell Cycle

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miRNAs are increasingly being implicated as key regulators of cell proliferation, apoptosis, and differentiation. miRNA-34c appears to play a crucial role in cancer pathogenesis wherein it exerts its effect as a tumor suppressor. However, the role of miR-34c in myoblast proliferation remains poorly understood. Here, we found that overexpression miR-34c inhibited myoblasts proliferation by reducing the protein and mRNA expression of cell cycle genes. In contrast, blocking the function of miR-34c promoted myoblasts proliferation and increased the protein and mRNA expression of cell cycle genes. Moreover, miR-34c directly targeted YY1 and inhibited its expression. Similar to overexpression miR-34c, knockdown of YY1 by siRNA suppressed myoblasts proliferation. Our study provides novel evidence for a role of miR-34c in inhibiting myoblasts proliferation by repressing YY1. Thus, miR-34c has the potential to be used to enhance skeletal muscle development and regeneration.

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“…In osteosarcoma, specific miRNA expression has been analyzed in tumor cell lines as well as in primary human samples and fixed specimens [10,11,12]. Multiple miRNAs including miR-199a-3p, miR-221, miR-34c and miR-16 have been implicated in the development of osteosarcoma, which function as tumor suppressors or oncogenes [13,14,15,16]. …”

Section: Introductionmentioning

confidence: 99%

MiR-142-3p Functions as a Potential Tumor Suppressor in Human Osteosarcoma by Targeting HMGA1

Wang

Jia

et al. 2014

Cell Physiol Biochem

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Background/Aims: Mounting evidence has shown that aberrant expression of miRNAs correlates with human cancers, and that miRNAs can function as tumor suppressors or oncogenes. Here, we investigated the role and mechanism of miR-142-3p in human osteosarcoma. Methods: We used quantitative real-time RT-PCR to measure the expression of miR-142-3p in human osteosarcoma cell lines and tissues. The roles of miR-142-3p in osteosarcoma development were studied using cultured HOS, MG63 and Saos-2 cells and tumor xenograft analyses in nude mice; their target genes were also investigated. Results: We found that miR-142-3p was significantly downregulated in osteosarcoma cell lines and clinical specimens. Overexpression of miR-142-3p suppressed osteosarcoma cell proliferation, migration and invasion, whereas miR-142-3p knockdown increased these parameters. The xenograft mouse model also revealed the suppressive effect of miR-142-3p on tumor growth. High mobility group AT-hook 1 (HMGA1) was identified as a target of miR-142-3p. Downregulation of HMGA1 induced effects on osteosarcoma cell lines similar to those induced by miR-142-3p. In contrast, restoration of HMGA1 abrogated the effects induced by miR-142-3p up-regulation. Conclusion: These results indicated that miR-142-3p may function as a tumor suppressor by targeting HMGA1 in osteosarcoma.

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MicroRNA-34c Inversely Couples the Biological Functions of the Runt-related Transcription Factor RUNX2 and the Tumor Suppressor p53 in Osteosarcoma

Cited by 93 publications

References 45 publications

Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle

Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle

miRNA-34c inhibits myoblasts proliferation by targeting YY1

MiR-142-3p Functions as a Potential Tumor Suppressor in Human Osteosarcoma by Targeting HMGA1

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