TY - JOUR
T1 - FGF-2 induces a failure of cell cycle progression in cells harboring amplified K-Ras, revealing new insights into oncogene-induced senescence
AU - Lund, Peder J.
AU - Lopes, Mariana
AU - Sidoli, Simone
AU - Coradin, Mariel
AU - Vitorino, Francisca Nathália de Luna
AU - da Cunha, Julia Pinheiro Chagas
AU - Garcia, Benjamin A.
N1 - Funding Information:
The authors thank Ivan Novaski for assistance with cell culture; Dr Payel Sen, Dr Marcelo Reis and Dr Hugo Armelin for revising the manuscript; and Greg Donahue and the Berger Lab for assistance with sequencing analysis. Funding was provided by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) grants #2011/22619-7 (J. P. C. C.), #2018/15553-9 (J. P. C. C.), #2013/07467-1, #2015/04867-4 (M. L.), #2016/ 24881-4 (M. L.), #2017/15835-1 (M. L.), and #2017/18344-9 (F. N. L. V.); the Crohn’s and Colitis Foundation (RFA#598467, P. J. L.); and the National Institutes of Health (2T32CA009140-41A1 to P. J. L., P30CA013330-47 and 1S10OD030286-01 to S. S., P01AG031862 and R01CA196539 to B. A. G.). S.S. acknowledges the Leukemia Research Foundation (Hollis Brownstein New Investigator Research Grant), AFAR (Sagol Network GerOmic Award), the Einstein Nathan Shock Center for the Biology of Aging, and Deerfield (Xseed Award). The funding agencies were not involved in study design, data collection and interpretation, or manuscript preparation.
Publisher Copyright:
© The Royal Society of Chemistry 2021.
PY - 2021/10
Y1 - 2021/10
N2 - Paradoxically, oncogenes that drive cell cycle progression may also trigger pathways leading to senescence, thereby inhibiting the growth of tumorigenic cells. Knowledge of how these pathways operate, and how tumor cells may evade these pathways, is important for understanding tumorigenesis. The Y1 cell line, which harbors an amplification of the proto-oncogene Ras, rapidly senesces in response to the mitogen fibroblast growth factor-2 (FGF-2). To gain a more complete picture of how FGF-2 promotes senescence, we employed a multi-omics approach to analyze histone modifications, mRNA and protein expression, and protein phosphorylation in Y1 cells treated with FGF-2. Compared to control cells treated with serum alone, FGF-2 caused a delayed accumulation of acetylation on histone H4 and higher levels of H3K27me3. Sequencing analysis revealed decreased expression of cell cycle-related genes with concomitant loss of H3K27ac. At the same time, FGF-2 promoted the expression of p21, various cytokines, and MAPK-related genes. Nuclear envelope proteins, particularly lamin B1, displayed increased phosphorylation in response to FGF-2. Proteome analysis suggested alterations in cellular metabolism, as evident by modulated expression of enzymes involved in purine biosynthesis, tRNA aminoacylation, and the TCA cycle. We propose that Y1 cells senesce due to an inability to progress through the cell cycle, which may stem from DNA damage or TGFb signaling. Altogether, the phenotype of Y1 cells is consistent with rapidly established oncogene-induced senescence, demonstrating the synergy between growth factors and oncogenes in driving senescence and bringing additional insight into this tumor suppressor mechanism.
AB - Paradoxically, oncogenes that drive cell cycle progression may also trigger pathways leading to senescence, thereby inhibiting the growth of tumorigenic cells. Knowledge of how these pathways operate, and how tumor cells may evade these pathways, is important for understanding tumorigenesis. The Y1 cell line, which harbors an amplification of the proto-oncogene Ras, rapidly senesces in response to the mitogen fibroblast growth factor-2 (FGF-2). To gain a more complete picture of how FGF-2 promotes senescence, we employed a multi-omics approach to analyze histone modifications, mRNA and protein expression, and protein phosphorylation in Y1 cells treated with FGF-2. Compared to control cells treated with serum alone, FGF-2 caused a delayed accumulation of acetylation on histone H4 and higher levels of H3K27me3. Sequencing analysis revealed decreased expression of cell cycle-related genes with concomitant loss of H3K27ac. At the same time, FGF-2 promoted the expression of p21, various cytokines, and MAPK-related genes. Nuclear envelope proteins, particularly lamin B1, displayed increased phosphorylation in response to FGF-2. Proteome analysis suggested alterations in cellular metabolism, as evident by modulated expression of enzymes involved in purine biosynthesis, tRNA aminoacylation, and the TCA cycle. We propose that Y1 cells senesce due to an inability to progress through the cell cycle, which may stem from DNA damage or TGFb signaling. Altogether, the phenotype of Y1 cells is consistent with rapidly established oncogene-induced senescence, demonstrating the synergy between growth factors and oncogenes in driving senescence and bringing additional insight into this tumor suppressor mechanism.
UR - http://www.scopus.com/inward/record.url?scp=85116971171&partnerID=8YFLogxK
U2 - 10.1039/d1mo00019e
DO - 10.1039/d1mo00019e
M3 - Article
C2 - 34636387
AN - SCOPUS:85116971171
SN - 2515-4184
VL - 17
SP - 725
EP - 739
JO - Molecular Omics
JF - Molecular Omics
IS - 5
ER -