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8 results on '"Giovanni Perini"'

1. The transcriptional co-repressor Runx1t1 is essential for MYCN-driven neuroblastoma tumorigenesis

Author

Jayne E. Murray, Emanuele Valli, Giorgio Milazzo, Chelsea Mayoh, Andrew J. Gifford, Jamie I. Fletcher, Chengyuan Xue, Nisitha Jayatilleke, Firoozeh Salehzadeh, Laura D. Gamble, Jourdin R. C. Rouaen, Daniel R. Carter, Helen Forgham, Eric O. Sekyere, Joanna Keating, Georgina Eden, Sophie Allan, Stephanie Alfred, Frances K. Kusuma, Ashleigh Clark, Hannah Webber, Amanda J. Russell, Antoine de Weck, Benjamin T. Kile, Martina Santulli, Piergiuseppe De Rosa, Emmy D. G. Fleuren, Weiman Gao, Lorna Wilkinson-White, Jason K. K. Low, Joel P. Mackay, Glenn M. Marshall, Douglas J. Hilton, Federico M. Giorgi, Jan Koster, Giovanni Perini, Michelle Haber, and Murray D. Norris

Subjects
Science
Abstract

Abstract MYCN oncogene amplification is frequently observed in aggressive childhood neuroblastoma. Using an unbiased large-scale mutagenesis screen in neuroblastoma-prone transgenic mice, we identify a single germline point mutation in the transcriptional corepressor Runx1t1, which abolishes MYCN-driven tumorigenesis. This loss-of-function mutation disrupts a highly conserved zinc finger domain within Runx1t1. Deletion of one Runx1t1 allele in an independent Runx1t1 knockout mouse model is also sufficient to prevent MYCN-driven neuroblastoma development, and reverse ganglia hyperplasia, a known pre-requisite for tumorigenesis. Silencing RUNX1T1 in human neuroblastoma cells decreases colony formation in vitro, and inhibits tumor growth in vivo. Moreover, RUNX1T1 knockdown inhibits the viability of PAX3-FOXO1 fusion-driven rhabdomyosarcoma and MYC-driven small cell lung cancer cells. Despite the role of Runx1t1 in MYCN-driven tumorigenesis neither gene directly regulates the other. We show RUNX1T1 forms part of a transcriptional LSD1-CoREST3-HDAC repressive complex recruited by HAND2 to enhancer regions to regulate chromatin accessibility and cell-fate pathway genes.

Published
2024
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2. MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma

Author

Ling Tao, Mahmoud A. Mohammad, Giorgio Milazzo, Myrthala Moreno-Smith, Tajhal D. Patel, Barry Zorman, Andrew Badachhape, Blanca E. Hernandez, Amber B. Wolf, Zihua Zeng, Jennifer H. Foster, Sara Aloisi, Pavel Sumazin, Youli Zu, John Hicks, Ketan B. Ghaghada, Nagireddy Putluri, Giovanni Perini, Cristian Coarfa, and Eveline Barbieri

Subjects
Science
Abstract

Half of high-risk neuroblastoma patients have MYCN amplification. Here, the authors show that MYCN induces fatty acid uptake and synthesis to support neuroblastoma and inhibition of a fatty acid transporter impairs tumor progression in preclinical models.

Published
2022
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3. Restoration of the molecular clock is tumor suppressive in neuroblastoma

Author

Myrthala Moreno-Smith, Giorgio Milazzo, Ling Tao, Baharan Fekry, Bokai Zhu, Mahmoud A. Mohammad, Simone Di Giacomo, Roshan Borkar, Karthik Reddy Kami Reddy, Mario Capasso, Sanjeev A. Vasudevan, Pavel Sumazin, John Hicks, Nagireddy Putluri, Giovanni Perini, Kristin Eckel-Mahan, Thomas P. Burris, and Eveline Barbieri

Subjects
Science
Abstract

MYCN is frequently amplified in neuroblastomas. Here, the authors show that MYCN disrupts the molecular clock by downregulating clock activator RORα and that the reactivation of RORα restores BMAL1 activity, and inhibits lipid metabolism and neuroblastoma growth

Published
2021
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4. PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis

Author

Slim Mzoughi, Jia Yi Fong, David Papadopoli, Cheryl M. Koh, Laura Hulea, Paolo Pigini, Federico Di Tullio, Giuseppe Andreacchio, Michal Marek Hoppe, Heike Wollmann, Diana Low, Matias J. Caldez, Yanfen Peng, Denis Torre, Julia N. Zhao, Oro Uchenunu, Gabriele Varano, Corina-Mihaela Motofeanu, Manikandan Lakshmanan, Shun Xie Teo, Cheng Mun Wun, Giovanni Perini, Soo Yong Tan, Chee Bing Ong, Muthafar Al-Haddawi, Ravisankar Rajarethinam, Susan Swee-Shan Hue, Soon Thye Lim, Choon Kiat Ong, Dachuan Huang, Siok-Bian Ng, Emily Bernstein, Dan Hasson, Keng Boon Wee, Philipp Kaldis, Anand Jeyasekharan, David Dominguez-sola, Ivan Topisirovic, and Ernesto Guccione

Subjects
Science
Abstract

The transcriptional regulator PRDM15 is expressed at low levels in normal tissues but overexpressed in B-cell lymphomas. Here, the authors show that PRDM15 depletion does not affect adult somatic cell homeostasis but leads to a metabolic crisis which impairs B-cell lymphomagenesis.

Published
2020
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5. The long noncoding RNA lncNB1 promotes tumorigenesis by interacting with ribosomal protein RPL35

Author

Pei Y. Liu, Andrew E. Tee, Giorgio Milazzo, Katherine M. Hannan, Jesper Maag, Sujanna Mondal, Bernard Atmadibrata, Nenad Bartonicek, Hui Peng, Nicholas Ho, Chelsea Mayoh, Roberto Ciaccio, Yuting Sun, Michelle J. Henderson, Jixuan Gao, Celine Everaert, Amy J. Hulme, Matthew Wong, Qing Lan, Belamy B. Cheung, Leming Shi, Jenny Y. Wang, Thorsten Simon, Matthias Fischer, Xu D. Zhang, Glenn M. Marshall, Murray D. Norris, Michelle Haber, Jo Vandesompele, Jinyan Li, Pieter Mestdagh, Ross D. Hannan, Marcel E. Dinger, Giovanni Perini, and Tao Liu

Subjects
Science
Abstract

MYCN amplification is common in neuroblastomas. Here, the authors identify a long noncoding RNA, lncNB1 in these cancers and show that it promotes tumorigenesis by binding to ribosomal protein, RPL35 to enhance E2F1 and DEPDC1B protein synthesis, which phosphorylates ERK to stabilise N-Myc.

Published
2019
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6. JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma

Author

Matthew Wong, Yuting Sun, Zhichao Xi, Giorgio Milazzo, Rebecca C. Poulos, Christoph Bartenhagen, Jessica L. Bell, Chelsea Mayoh, Nicholas Ho, Andrew E. Tee, Xiaoqiong Chen, Yang Li, Roberto Ciaccio, Pei Y. Liu, Chen C. Jiang, Qing Lan, Nisitha Jayatilleke, Belamy B. Cheung, Michelle Haber, Murray D. Norris, Xu D. Zhang, Glenn M. Marshall, Jenny Y. Wang, Stefan Hüttelmaier, Matthias Fischer, Jason W. H. Wong, Hongxi Xu, Giovanni Perini, Qihan Dong, Rani E. George, and Tao Liu

Subjects
Science
Abstract

Although the gain in chromosome 17q21-ter is commonly associated with neuroblastoma, it is not clear which gene of this region mediates tumorigenesis. Here, the authors are showing that JMJD6, which locates in that region, is a neuroblastoma tumorigenic factor.

Published
2019
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7. Restoration of the molecular clock is tumor suppressive in neuroblastoma

Author

Nagireddy Putluri, Eveline Barbieri, John Hicks, Karthik reddy kami reddy, Pavel Sumazin, Thomas P. Burris, Simone Di Giacomo, Baharan Fekry, Ling Tao, Bokai Zhu, Mario Capasso, Giorgio Milazzo, Giovanni Perini, Sanjeev A. Vasudevan, Myrthala Moreno-Smith, Kristin Eckel-Mahan, Mahmoud A. Mohammad, Roshan Borkar, Moreno-Smith M., Milazzo G., Tao L., Fekry B., Zhu B., Mohammad M.A., Di Giacomo S., Borkar R., Reddy K.R.K., Capasso M., Vasudevan S.A., Sumazin P., Hicks J., Putluri N., Perini G., Eckel-Mahan K., Burris T.P., Barbieri E., Moreno-Smith, M., Milazzo, G., Tao, L., Fekry, B., Zhu, B., Mohammad, M. A., Di Giacomo, S., Borkar, R., Reddy, K. R. K., Capasso, M., Vasudevan, S. A., Sumazin, P., Hicks, J., Putluri, N., Perini, G., Eckel-Mahan, K., Burris, T. P., and Barbieri, E.

Subjects
0301 basic medicine, General Physics and Astronomy, Stimulation, Antineoplastic Agent, Mice, Neuroblastoma, 0302 clinical medicine, MYCN, Promoter Regions, Genetic, Cancer, N-Myc Proto-Oncogene Protein, Multidisciplinary, Chemistry, ARNTL Transcription Factors, Nuclear Receptor Subfamily 1, Group F, Member 1, ARNTL Transcription Factor, 030220 oncology & carcinogenesis, Benzamides, Lipogenesis, Human, Agonist, Cell biology, tumor, medicine.drug_class, Cell Survival, Science, Repressor, Antineoplastic Agents, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Benzamide, Cell Line, Tumor, medicine, Oscillation (cell signaling), Animals, Humans, neoplasms, Activator (genetics), Animal, Lipogenesi, Promoter, General Chemistry, medicine.disease, Xenograft Model Antitumor Assays, 030104 developmental biology, Cancer research, RNA-seq
Abstract

MYCN activation is a hallmark of advanced neuroblastoma (NB) and a known master regulator of metabolic reprogramming, favoring NB adaptation to its microenvironment. We found that the expression of the main regulators of the molecular clock loops is profoundly disrupted in MYCN-amplified NB patients, and this disruption independently predicts poor clinical outcome. MYCN induces the expression of clock repressors and downregulates the one of clock activators by directly binding to their promoters. Ultimately, MYCN attenuates the molecular clock by suppressing BMAL1 expression and oscillation, thereby promoting cell survival. Reestablishment of the activity of the clock activator RORα via its genetic overexpression and its stimulation through the agonist SR1078, restores BMAL1 expression and oscillation, effectively blocks MYCN-mediated tumor growth and de novo lipogenesis, and sensitizes NB tumors to conventional chemotherapy. In conclusion, reactivation of RORα could serve as a therapeutic strategy for MYCN-amplified NBs by blocking the dysregulation of molecular clock and cell metabolism mediated by MYCN., MYCN is frequently amplified in neuroblastomas. Here, the authors show that MYCN disrupts the molecular clock by downregulating clock activator RORα and that the reactivation of RORα restores BMAL1 activity, and inhibits lipid metabolism and neuroblastoma growth

Published
2021

8. JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma

Author

Nisitha Jayatilleke, Giorgio Milazzo, Giovanni Perini, Andrew E. Tee, Michelle Haber, Hong-Xi Xu, Yang Li, Murray D. Norris, Matthew S. Wong, Zhichao Xi, Chen C. Jiang, Stefan Hüttelmaier, Xiaoqiong Chen, Roberto Ciaccio, Pei Y. Liu, Qihan Dong, Rebecca C. Poulos, Rani E. George, Belamy B. Cheung, Chelsea Mayoh, Yuting Sun, Jessica L. Bell, Glenn M. Marshall, Xu D. Zhang, Matthias Fischer, Tao Liu, Nicholas Ho, Qing Lan, Christoph Bartenhagen, Jenny Y. Wang, Jason W. H. Wong, Wong M., Sun Y., Xi Z., Milazzo G., Poulos R.C., Bartenhagen C., Bell J.L., Mayoh C., Ho N., Tee A.E., Chen X., Li Y., Ciaccio R., Liu P.Y., Jiang C.C., Lan Q., Jayatilleke N., Cheung B.B., Haber M., Norris M.D., Zhang X.D., Marshall G.M., Wang J.Y., Huttelmaier S., Fischer M., Wong J.W.H., Xu H., Perini G., Dong Q., George R.E., and Liu T.

Subjects
0301 basic medicine, Male, Jumonji Domain-Containing Histone Demethylases, Carcinogenesis, General Physics and Astronomy, Apoptosis, 02 engineering and technology, medicine.disease_cause, chemistry.chemical_compound, Mice, Neuroblastoma, Neuroblastoma, JMJD6, N-Myc, E2F2, BRD4, E2F2 Transcription Factor, lcsh:Science, E2F2, Cancer, Regulation of gene expression, Mice, Inbred BALB C, Multidisciplinary, Histone deacetylase inhibitor, 021001 nanoscience & nanotechnology, Gene Expression Regulation, Neoplastic, Female, 0210 nano-technology, Protein Binding, medicine.drug_class, Science, Receptors, Cell Surface, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Proto-Oncogene Proteins c-myc, Paediatric cancer, 03 medical and health sciences, Panobinostat, Embryonal neoplasms, medicine, Animals, Humans, neoplasms, Cell Proliferation, General Chemistry, medicine.disease, Histone Deacetylase Inhibitors, 030104 developmental biology, chemistry, Tumor progression, Cancer research, lcsh:Q, N-Myc
Abstract

Chromosome 17q21-ter is commonly gained in neuroblastoma, but it is unclear which gene in the region is important for tumorigenesis. The JMJD6 gene at 17q21-ter activates gene transcription. Here we show that JMJD6 forms protein complexes with N-Myc and BRD4, and is important for E2F2, N-Myc and c-Myc transcription. Knocking down JMJD6 reduces neuroblastoma cell proliferation and survival in vitro and tumor progression in mice, and high levels of JMJD6 expression in human neuroblastoma tissues independently predict poor patient prognosis. In addition, JMJD6 gene is associated with transcriptional super-enhancers. Combination therapy with the CDK7/super-enhancer inhibitor THZ1 and the histone deacetylase inhibitor panobinostat synergistically reduces JMJD6, E2F2, N-Myc, c-Myc expression, induces apoptosis in vitro and leads to neuroblastoma tumor regression in mice, which are significantly reversed by forced JMJD6 over-expression. Our findings therefore identify JMJD6 as a neuroblastoma tumorigenesis factor, and the combination therapy as a treatment strategy., Although the gain in chromosome 17q21-ter is commonly associated with neuroblastoma, it is not clear which gene of this region mediates tumorigenesis. Here, the authors are showing that JMJD6, which locates in that region, is a neuroblastoma tumorigenic factor.

Published
2019

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