MANCR lncRNA Modulates Cell-Cycle Progression and Metastasis by Cis-Regulation of Nuclear Rho-GEF
Year: 2024
Type: article
Abstract: A significant number of the genetic alterations observed in cancer patients lie within nonprotein-coding segments of the genome, including regions coding for long noncoding RNAs (lncRNAs). LncRNAs display aberrant expression in breast cancer (BrCa), but the functional implications of this altered expression remain to be elucidated. By performing transcriptome screen in a triple negative BrCa (TNBC) isogenic 2D and 3D spheroid model, we observed aberrant expression of >1000 lncRNAs during BrCa progression. The chromatin-associated lncRNA MANCR shows elevated expression in metastatic TNBC. MANCR is upregulated in response to cellular stress and modulates DNA repair and cell proliferation. MANCR promotes metastasis as MANCR-depleted cells show reduced cell migration, invasion, and wound healing in vitro, and reduced metastatic lung colonization in xenograft experiments in vivo. Transcriptome analyses reveal that MANCR modulates expression and pre-mRNA splicing of genes, controlling DNA repair and checkpoint response. MANCR promotes the transcription of NET1A, a Rho-GEF that regulates DNA damage checkpoint and metastatic processes in cis, by differential promoter usage. Experiments suggest that MANCR regulates the expression of cancer-associated genes by modulating the association of various transcription factors and RNA-binding proteins. Our results identified the metastasis-promoting activities of MANCR in TNBC by cis-regulation of gene expression.
Source: Molecular and Cellular Biology
Authors: Deepak K. Singh, Zhengmin Cong, You Jin Song, Minxue Liu, Ritu Chaudhary, Dazhen Liu, Yu Wang, Rishabh Prasanth, Rajendra K C, Simon Lizarazo, Miriam Akhnoukh, Omid Gholamalamdari, Anurupa Moitra, Lisa M. Jenkins, Rohit Bhargava, Erik R. Nelson, Kevin Van Bortle, Supriya G. Prasanth, Kannanganattu V. Prasanth
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, U.S. Department of Defense, University of Pennsylvania, Indiana University-Purdue University Indianapolis, University of Illinois at Urbana-Champaign, National Institute on Aging, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences
Awards: G1952805926, G2662092234, Characterization of nuclear-retained RNA-mediated gene regulatory mechanisms, G4119534169, G4263525803, G442447162, G4473626617, G5457587840, Role of BEN domain proteins in chromatin organization and gene expression, G6776838423, CAREER: Establishment of Replication Timing and Patterning in Mammalian Cells, Science and Technology Center for Quantitative Cell Biology
OpenAlex ID: W4401515705