Abstract
Transforming growth factor-α (TGF-α)-induced proliferation and transforming growth factor-β (TGF-β)-mediated quiescence are intricately balanced in normal lung-tissue homeostasis but are deregulated during neoplastic progression of lung cancer. Here, we show that Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2), a novel MYC-interacting transcriptional modulator, responds to TGF-α induction and TGF-β suppression to orchestrate cellular proliferation and quiescence, respectively. Upon TGF-α induction, CITED2 was induced by MYC and further modulated MYC-mediated transcription in a feed-forward manner. CITED2 recruited p300 to promote MYC-p300-mediated transactivation of E2F3, leading to increased G1/S cell cycle progression. Moreover, CITED2 inhibited cellular quiescence by enhancing MYC-mediated suppression of p21CIP1. CITED2 interacted with histone deacetylase 1 (HDAC1) and potentiated MYC–HDAC1 complex formation. TGF-β stimulation provoked downregulation of CITED2, which abrogated MYC-HDAC1-mediated p21CIP1 suppression, causing cellular quiescence. Ectopic CITED2 expression enhanced tumor growth in nude mice; furthermore, CITED2 knockdown caused tumor shrinkage and increased overall host mouse survival rates. Expression of CITED2/MYC/E2F3/p21CIP1 signaling molecules was associated with poor prognosis of lung cancer patients. Thus, CITED2 functions as a molecular switch of TGF-α and TGF-β-induced growth control, and MYC-CITED2 signaling axis provides a new index for predicting clinical outcome.
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Abbreviations
- CITED2:
-
Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2
- TGF-α:
-
transforming growth factor alpha
- TGF-β:
-
transforming growth factor beta
- NSCLC:
-
non-small-cell lung cancer
- EGFR:
-
epidermal growth factor receptor
- TGFBRI:
-
transforming growth factor beta receptor I
- TGFBRII:
-
transforming growth factor beta receptor II
- p300:
-
E1A binding protein p300
- HDAC1:
-
histone deacetylase 1
- Dox:
-
doxycycline
- eGFP:
-
enhanced green fluorescent protein
- shRNA:
-
short hairpin RNA
- GST:
-
glutathione S-transferase
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Acknowledgements
We thank Dr. Scott Kominsky and Dr. Kristin Webber for their discussion. This research was supported by the Institute of Biomedical Sciences, Academia Sinica, National Yang-Ming University, and the National Science Council (NSC100–2325-B-010–011, NSC100–3112-B-010–004 and NSC100–2321-B-010–021), Executive Yuan, Taiwan, ROC.
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Chou, YT., Hsieh, CH., Chiou, SH. et al. CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence. Cell Death Differ 19, 2015–2028 (2012). https://doi.org/10.1038/cdd.2012.91
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DOI: https://doi.org/10.1038/cdd.2012.91
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