Review
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. May 24, 2020; 11(5): 260-274
Published online May 24, 2020. doi: 10.5306/wjco.v11.i5.260
CITED2 and the modulation of the hypoxic response in cancer
Mónica T Fernandes, Sofia M Calado, Leonardo Mendes-Silva, José Bragança
Mónica T Fernandes, School of Health, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
Mónica T Fernandes, Sofia M Calado, Leonardo Mendes-Silva, José Bragança, Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
Mónica T Fernandes, Sofia M Calado, Leonardo Mendes-Silva, José Bragança, Algarve Biomedical Centre, Faro 8005-139, Portugal
Leonardo Mendes-Silva, José Bragança, Department of Biomedical Sciences and Medicine, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
Author contributions: Fernandes MT and Bragança J conceived this article and its contents; Fernandes MT, Calado SM and Mendes-Silva L wrote the first draft of the manuscript; Mendes-Silva L prepared the figures; Bragança J revised the manuscript; and all authors approved the final version.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: José Bragança, PhD, Assistant Professor, Department of Biomedical Sciences and Medicine, CBMR-Centre for BioMedical Research, Universidade do Algarve, Campus of Gambelas, Building 8, Room 2.22, Faro 8005-139, Portugal. jebraganca@ualg.pt
Received: February 27, 2020
Peer-review started: February 27, 2020
First decision: April 7, 2020
Revised: April 13, 2020
Accepted: May 12, 2020
Article in press: May 12, 2020
Published online: May 24, 2020
Abstract

CITED2 (CBP/p300-interacting transactivator with Glu/Asp-rich C-terminal domain, 2) is a ubiquitously expressed protein exhibiting a high affinity for the CH1 domain of the transcriptional co-activators CBP/p300, for which it competes with hypoxia-inducible factors (HIFs). CITED2 is particularly efficient in the inhibition of HIF-1α-dependent transcription in different contexts, ranging from organ development and metabolic homeostasis to tissue regeneration and immunity, being also potentially involved in various other physiological processes. In addition, CITED2 plays an important role in inhibiting HIF in some diseases, including kidney and heart diseases and type 2-diabetes. In the particular case of cancer, CITED2 either functions by promoting or suppressing cancer development depending on the context and type of tumors. For instance, CITED2 overexpression promotes breast and prostate cancers, as well as acute myeloid leukemia, while its expression is downregulated to sustain colorectal cancer and hepatocellular carcinoma. In addition, the role of CITED2 in the maintenance of cancer stem cells reveals its potential as a target in non-small cell lung carcinoma and acute myeloid leukemia, for example. But besides the wide body of evidence linking both CITED2 and HIF signaling to carcinogenesis, little data is available regarding CITED2 role as a negative regulator of HIF-1α specifically in cancer. Therefore, comprehensive studies exploring further the interactions of these two important mediators in cancer-specific models are sorely needed and this can potentially lead to the development of novel targeted therapies.

Keywords: Cancer, Cancer stem cell, CBP/p300, CITED2, Hypoxia-inducible factors 1α, Hypoxia, Leukemia, Tumor

Core tip: Hypoxia is a common feature of many cancers. In response to hypoxia, hypoxia-inducible factor 1 (HIF-1) is stabilized and activates downstream target-genes participating in crucial aspects of cancer biology, such as angiogenesis, cell survival, glucose metabolism and invasion. CITED2 is a negative regulator of HIF with demonstrated roles in various types of cancer. Therefore, CITED2 can potentially modulate HIF effects in cancer and constitute a novel target for therapies. Herein, we compile the roles reported for CITED2 in health and disease, namely through the modulation of HIF activity. We also discuss the various context-dependent roles for CITED2 in cancer.