TY - JOUR
T1 - Integrated multi-omics analysis of RB-loss identifies widespread cellular programming and synthetic weaknesses
AU - Rajasekaran, Swetha
AU - Siddiqui, Jalal
AU - Rakijas, Jessica
AU - Nicolay, Brandon
AU - Lin, Chenyu
AU - Khan, Eshan
AU - Patel, Rahi
AU - Morris, Robert
AU - Wyler, Emanuel
AU - Boukhali, Myriam
AU - Balasubramanyam, Jayashree
AU - Ranjith Kumar, R.
AU - Van Rechem, Capucine
AU - Vogel, Christine
AU - Elchuri, Sailaja V.
AU - Landthaler, Markus
AU - Obermayer, Benedikt
AU - Haas, Wilhelm
AU - Dyson, Nicholas
AU - Miles, Wayne
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Inactivation of RB is one of the hallmarks of cancer, however gaps remain in our understanding of how RB-loss changes human cells. Here we show that pRB-depletion results in cellular reprogramming, we quantitatively measured how RB-depletion altered the transcriptional, proteomic and metabolic output of non-tumorigenic RPE1 human cells. These profiles identified widespread changes in metabolic and cell stress response factors previously linked to E2F function. In addition, we find a number of additional pathways that are sensitive to RB-depletion that are not E2F-regulated that may represent compensatory mechanisms to support the growth of RB-depleted cells. To determine whether these molecular changes are also present in RB1−/− tumors, we compared these results to Retinoblastoma and Small Cell Lung Cancer data, and identified widespread conservation of alterations found in RPE1 cells. To define which of these changes contribute to the growth of cells with de-regulated E2F activity, we assayed how inhibiting or depleting these proteins affected the growth of RB1−/− cells and of Drosophila E2f1-RNAi models in vivo. From this analysis, we identify key metabolic pathways that are essential for the growth of pRB-deleted human cells.
AB - Inactivation of RB is one of the hallmarks of cancer, however gaps remain in our understanding of how RB-loss changes human cells. Here we show that pRB-depletion results in cellular reprogramming, we quantitatively measured how RB-depletion altered the transcriptional, proteomic and metabolic output of non-tumorigenic RPE1 human cells. These profiles identified widespread changes in metabolic and cell stress response factors previously linked to E2F function. In addition, we find a number of additional pathways that are sensitive to RB-depletion that are not E2F-regulated that may represent compensatory mechanisms to support the growth of RB-depleted cells. To determine whether these molecular changes are also present in RB1−/− tumors, we compared these results to Retinoblastoma and Small Cell Lung Cancer data, and identified widespread conservation of alterations found in RPE1 cells. To define which of these changes contribute to the growth of cells with de-regulated E2F activity, we assayed how inhibiting or depleting these proteins affected the growth of RB1−/− cells and of Drosophila E2f1-RNAi models in vivo. From this analysis, we identify key metabolic pathways that are essential for the growth of pRB-deleted human cells.
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U2 - 10.1038/s42003-021-02495-2
DO - 10.1038/s42003-021-02495-2
M3 - Article
C2 - 34404904
AN - SCOPUS:85113175879
SN - 2399-3642
VL - 4
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 977
ER -