The Noncoding RNA MALAT1 Is a Critical Regulator of the Metastasis Phenotype of Lung Cancer Cells
Tony Gutschner,Monika Hämmerle,Moritz Eißmann,Jeff Hsu,Youngsoo Kim,Gene Hung,Alexey S. Revenko,Gayatri Arun,Marion Stentrup,Matthias Groß,Martin Zörnig,A. Robert MacLeod,David L. Spector,Sven Diederichs +13 more
TLDR
A loss-of-function model unravels the active function of MALAT1 as a regulator of gene expression governing hallmarks of lung cancer metastasis with this ncRNA serving as both predictive marker and therapeutic target.Abstract:
The long non-coding RNA MALAT1, also known as MALAT-1 or NEAT2, is a highly conserved nuclear ncRNA and a predictive marker for metastasis development in lung cancer. To uncover its functional importance, we developed a MALAT1 knockout model in human lung tumor cells by genomically integrating RNA destabilizing elements using Zinc Finger Nucleases. The achieved 1000-fold MALAT1 silencing provides a unique loss-of-function model. Proposed mechanisms of action include regulation of splicing or gene expression. In lung cancer, MALAT1 does not alter alternative splicing but actively regulates gene expression including a set of metastasis-associated genes. Consequently, MALAT1-deficient cells are impaired in migration and form fewer tumor nodules in a mouse xenograft. Antisense oligonucleotides blocking MALAT1 prevent metastasis formation after tumor implantation. Thus, targeting MALAT1 with antisense oligonucleotides provides a potential therapeutic approach to prevent lung cancer metastasis with MALAT1 serving as both, predictive marker and therapeutic target. Lastly, regulating gene expression, but not alternative splicing is the critical function of MALAT1 in lung cancer metastasis. In summary, ten years after the discovery of the lncRNA MALAT1 as a biomarker for lung cancer metastasis, our loss-of-function model unravels the active function of MALAT1 as a regulator of gene expression governing hallmarks of lung cancer metastasis.read more
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RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells.
A. Rasim Barutcu,Deli Hong,Bryan R. Lajoie,Rachel Patton McCord,Andre J. van Wijnen,Jane B. Lian,Janet L. Stein,Job Dekker,Anthony N. Imbalzano,Gary S. Stein,Gary S. Stein +10 more
TL;DR: An architectural role for RUNX1 in fine-tuning local interactions rather than in global organization is suggested, providing novel insight into RunX1-mediated perturbations of higher-order genome organization that are functionally linked with RUNx1-dependent compromised gene expression in breast cancer cells.
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From biomarkers to therapeutic targets—the promises and perils of long non-coding RNAs in cancer
TL;DR: Prime examples of lncRNAs that serve as marker for cancer progression or therapy response and which might represent promising therapeutic targets are highlighted and introduced.
Journal ArticleDOI
Knockdown of long non-coding RNA MALAT1 increases the blood–tumor barrier permeability by up-regulating miR-140
Jun Ma,Ping Wang,Yilong Yao,Yunhui Liu,Zhen Li,Xiaobai Liu,Zhiqing Li,Xihe Zhao,Zhuo Xi,Hao Teng,Jing Liu,Yixue Xue +11 more
TL;DR: The fact that knockdown of MALAT1 resulted in the increased permeability of BTB, which might contribute to establishing potential therapeutic strategies for human gliomas, is demonstrated.
Journal ArticleDOI
HULC cooperates with MALAT1 to aggravate liver cancer stem cells growth through telomere repeat-binding factor 2.
TL;DR: The demonstrations suggest that haploinsufficiency of HULC/MALAT1 plays an important role in malignant growth of liver cancer stem cell and the interaction between RFC and PCNA or between CDK2 and CyclinE, the telomerase activity and the microsatellite instability (MSI) are significantly increased in the Liver cancer stem cells.
Journal ArticleDOI
'Lnc'-ing Wnt in female reproductive cancers: therapeutic potential of long non-coding RNAs in Wnt signalling.
Mei S Ong,Wanpei Cai,Yi Yuan,Hin Chong Leong,Tuan Zea Tan,Asad Mohammad,Ming L You,Frank Arfuso,Boon Cher Goh,Sudha Warrier,Sudha Warrier,Gautam Sethi,Gautam Sethi,Nicholas S. Tolwinski,Nicholas S. Tolwinski,Peter E. Lobie,Peter E. Lobie,Celestial T. Yap,Celestial T. Yap,Shing Chuan Hooi,Ruby Yun-Ju Huang,Alan Prem Kumar +21 more
TL;DR: A critical summary of the respective roles and cellular functions of Wnt‐associated lnc RNAs in female reproductive cancers is provided and the potential of circulating cell‐free lncRNAs as diagnostic markers and lncRNAAs as therapeutic targets is explored.
References
More filters
Journal ArticleDOI
The hallmarks of cancer.
TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.
Journal ArticleDOI
Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis
Rajnish A. Gupta,Nilay Shah,Kevin C. Wang,Jeewon Kim,Hugo M. Horlings,David J. Wong,Miao-Chih Tsai,Tiffany Hung,Pedram Argani,John L. Rinn,Yulei Wang,Pius Brzoska,Benjamin Kong,Rui-Chun Li,Robert B. West,Marc J. van de Vijver,Saraswati Sukumar,Howard Y. Chang +17 more
TL;DR: It is shown that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression, indicating that l incRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
Journal ArticleDOI
The Transcriptional Landscape of the Mammalian Genome
Piero Carninci,Takeya Kasukawa,Shintaro Katayama,Julian Gough,Martin C. Frith,N. Maeda,Rieko Oyama,Timothy Ravasi,Boris Lenhard,Christine A. Wells,Christine A. Wells,Rimantas Kodzius,Kazuro Shimokawa,Vladimir B. Bajic,Steven E. Brenner,Serge Batalov,Alistair R. R. Forrest,Mihaela Zavolan,Melissa J. Davis,Laurens G. Wilming,Vassilis Aidinis,Jonathan E. Allen,Alberto Ambesi-Impiombato,Rolf Apweiler,Rajith N. Aturaliya,Timothy L. Bailey,Mukesh Bansal,Laura L. Baxter,Kirk W. Beisel,T. Bersano,Hidemasa Bono,Alistair M. Chalk,Kuo Ping Chiu,V. Choudhary,Alan Christoffels,D. R. Clutterbuck,Mark L. Crowe,Emiliano Dalla,Brian P. Dalrymple,Bernard de Bono,G. Della Gatta,Diego di Bernardo,Thomas A. Down,Pär G. Engström,Michela Fagiolini,Geoffrey J. Faulkner,Colin F. Fletcher,T. Fukushima,Masaaki Furuno,Sugiko Futaki,Manuela Gariboldi,P. Georgii-Hemming,Thomas R. Gingeras,Takashi Gojobori,Richard E. Green,Stefano Gustincich,Matthias Harbers,Yoshitaka Hayashi,Takao K. Hensch,Nobutaka Hirokawa,David E. Hill,Lukasz Huminiecki,M. Iacono,Kazuho Ikeo,Atsushi Iwama,T. Ishikawa,M. Jakt,Alexander Kanapin,Masaru Katoh,Yuka Imamura Kawasawa,Janet Kelso,Hiroshi Kitamura,Hiroaki Kitano,George Kollias,S. P. T. Krishnan,Adele Kruger,Sarah K. Kummerfeld,Igor V. Kurochkin,Liana F. Lareau,Dejan Lazarevic,Leonard Lipovich,Jinfeng Liu,Sabino Liuni,Sean McWilliam,M. Madan Babu,Martin Madera,Luigi Marchionni,Hideo Matsuda,Shu-ichi Matsuzawa,Harukata Miki,Flavio Mignone,Sou Miyake,Ken A. Morris,Salim Mottagui-Tabar,Salim Mottagui-Tabar,Nicola Mulder,Naoko Nakano,Hiromitsu Nakauchi,P. Ng,Roland Nilsson,S. Nishiguchi,Seishi Nishikawa,Franco Nori,Osamu Ohara,Yasushi Okazaki,Valerio Orlando,Ken C Pang,William J. Pavan,Giulio Pavesi,Graziano Pesole,Nikolai Petrovsky,Silvano Piazza,Jonathan C. Reed,James F. Reid,Brian Z. Ring,M. Ringwald,Burkhard Rost,Yijun Ruan,Steven L. Salzberg,Albin Sandelin,Claudio Schneider,Christian Schönbach,K. Sekiguchi,Colin A. Semple,Shigeto Seno,Luca Sessa,Y. Sheng,Y. Shibata,Hiroshi Shimada,Kiyo Shimada,D. Silva,B. Sinclair,Silke Sperling,Elia Stupka,Koji Sugiura,Razvan Sultana,Yoichi Takenaka,Kohei Taki,K. Tammoja,Sin Lam Tan,S. Tang,Martin S. Taylor,Jesper Tegnér,Sarah A. Teichmann,Hiroki R. Ueda,Erik van Nimwegen,Roberto Verardo,Chia-Lin Wei,Ken Yagi,H. Yamanishi,E. Zabarovsky,S. Zhu,Andreas Zimmer,Winston Hide,Carol J. Bult,Sean M. Grimmond,Rohan D. Teasdale,Edison T. Liu,Vladimir Brusic,John Quackenbush,Claes Wahlestedt,Claes Wahlestedt,John S. Mattick,David A. Hume,C. Kai,D. Sasaki,Yasuhiro Tomaru,S. Fukuda,Mutsumi Kanamori-Katayama,M. Suzuki,Junken Aoki,Taku Arakawa,J. Iida,Kengo Imamura,Masayoshi Itoh,T. Kato,Hideya Kawaji,N. Kawagashira,Tsugumi Kawashima,M. Kojima,S. Kondo,Hideaki Konno,K. Nakano,Noriko Ninomiya,T. Nishio,M. Okada,Charles Plessy,K. Shibata,Toshiyuki Shiraki,S. Suzuki,Michihira Tagami,Kazunori Waki,Akira Watahiki,Yuko Okamura-Oho,Harukazu Suzuki,Jun Kawai,Yoshihide Hayashizaki,Yoshihide Hayashizaki +197 more
TL;DR: Detailed polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
Journal ArticleDOI
Long Noncoding RNA as Modular Scaffold of Histone Modification Complexes
Miao-Chih Tsai,Ohad Manor,Yue Wan,Nima Mosammaparast,Jordon K. Wang,Fei Lan,Yang Shi,Eran Segal,Howard Y. Chang +8 more
TL;DR: The results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, thereby specifying the pattern of histone modifications on target genes.
Journal ArticleDOI
RNA Maps Reveal New RNA Classes and a Possible Function for Pervasive Transcription
Philipp Kapranov,Jill Cheng,Sujit Dike,David A. Nix,Radharani Duttagupta,Aarron T. Willingham,Peter F. Stadler,Jana Hertel,Jörg Hackermüller,Ivo L. Hofacker,Ian Bell,Evelyn Cheung,Jorg Drenkow,Erica Dumais,Sandeep Patel,Gregg Helt,Madhavan Ganesh,Srinka Ghosh,Antonio Piccolboni,Victor Sementchenko,Hari Tammana,Thomas R. Gingeras +21 more
TL;DR: Three potentially functional classes of RNAs have been identified, two of which are syntenically conserved and correlate with the expression state of protein-coding genes and support a highly interleaved organization of the human transcriptome.
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