CITED2 and the modulation of the hypoxic response in cancer

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

Figure 1

Structure of CITED2 and its interplay with hypoxia-inducible factors to modulate the response to hypoxia. A: Schematic representation of CITED2, hypoxia-inducible factor (HIF)-1α and CBP/p300. The conserved regions amongst CITED family members, and the serine-glycine rich junction domain unique to CITED2 are indicated. Conserved regions 2 is the domain that characterizes the CITED proteins that contains a potent transactivation domain (TAD), which is responsible for the physical interaction with the domain CH1 of CBP/p300, also represented. HIF-1α has two TADs, namely, a N-terminal TAD and a C-terminal TAD, which are responsible for the transcriptional activity under hypoxia. To this end, HIF-1α binds to the CH1 region of p300, but CITED2 was shown to compete out HIF-1α for the binding to the same region, and to interfere with hypoxia-driven transcription; B: Model for CITED2, HIF-1α and CBP/p300 in hypoxia-responsive gene regulation. In normal levels of oxygen (normoxia), HIF-1α is hydroxylated at two proline residues within its oxygen-dependent degradation domain, which marks HIF-1α for proteasome degradation. In normoxia, CITED2 binds to CBP/p300 in the nucleus regulating the expression of target-gene. In addition, part of CITED2 proteins is ubiquitinated by FBXL5 and degraded by the proteasome. In hypoxia, HIF-1α is no longer hydroxylated, which prevents its degradation by the proteasome. Consequently, HIF-1α translocate and accumulates in the nucleus to associate with the HIFβ subunit to bind to specific Hypoxia-Response Elements in hypoxia-regulated genes. CITED2 competes with HIF-1α for the binding to the CH1 region of CBP/p300 and interferes with hypoxia-driven transcription. CR: Conserved regions; SRJ: Serine-glycine rich junction; TAD: Transactivation domain; HIF: Hypoxia-inducible factor; NAD: N-terminal TAD; CAD: C-terminal TAD.

Figure 2

Roles of CITED2 in homeostasis and cancer. CITED2-dependent modulation of hypoxia-inducible factor (HIF) is fine-tuned to control physiological processes such as development, tissue regeneration and immunity. Abrogation of CITED2/HIF-1α homeostasis may lead to the initiation, and/or disease progression depending on the cellular context. Cancer may be one these diseases, in which CITED2 and HIF-1α intervene to control tumor growth, drug resistance and metastization. HIF: Hypoxia-inducible factor.