NCOA4 (Nuclear Receptor Coactivator 4)

2008-10-01   Dario de Biase , Luca Morandi , Giovanni Tallini 

Bologna University School of Medicine, Anatomia Patologica, Ospedale Bellaria, Via Altura 3, 40139 Bologna, Italy





10 exons, 3431bp.


Isoforms due to alternative splicing.



Two isoforms:
- Isoform alfa (614 aa, mass around 70kD)
- Isoform beta: missing of aa 239-565 (mass around 32kD)


NCOA4 is widely expressed in several tissues, including testis, adrenal and thyroid glands, thymus, prostate. A truncated NCOA4 corresponding to the beta isoform is fused to RET exon 12 and is aberrantly expressed in papillary thyroid carcinoma as a consequence of intrachromosomal rearrangements at 10q11.2 (RET/NCOA4).


NCOA4 is involved in the androgen receptor signaling pathway and in the development of the male gonade. It is a ligand-dependent associated protein for the androgen receptor (AR), that functions as coactivator to enhance AR transcriptional activity (7-10 fold in human prostate cancer cells) and protein stability. NCOA4 also enhances the agonist activity of anti-androgens in human prostate cancer cells (3-30 fold in the prostate cancer cell line DU145), with relevant implications for hormonal treatment of prostate cancer. Albeit to a lesser degree (up to 2-fold), NCO4 also enhances transcription activity of other steroid receptors, such as glucocorticoid receptor (GR), progesterone receptor (PR) and oestrogen receptor (ER).
In addition to the interaction with steroid hormone receptors, NCOA4 functions as coactivator of peroxisome proliferator-activated receptor gamma (PPARG). PPARG is a peroxisome proliferator-activated receptor and as such belongs to the nuclear hormone receptor superfamily. PPARG is highly expressed in adipose tissue (were it is involved in adipogenesis and in the regulation of adipocyte-specific genes), as well as in other human tissues. Interestingly, PPARG is rearranged with PAX8 in a subset of follicular thyroid tumors.
Unlike the AR-NCOA4 interaction, which requires the presence of androgen, the PPARG-NCOA4 interaction can occur in the absence of exogenous ligand. However, the presence of the ligand enhances PPARG-NCOA4 transactivation and NCOA4 is thus regarded as a ligand-enhanced coactivator of PPARG.
Atlas Image
Ligand-specific interaction between AR (Androgen receptor), NCOA4, and the androgen receptor ligand DHT (dihydrotestosterone).



LINE S94L; F154L; C350R; P474R; L561P.


NCOA4 breakpoint for rearrangement to form RET/NCOA4 oncogene at cDNA bp791, corresponding to aa 238-239.

Implicated in

Entity name
inv(10)(q11q11) with RET/NCOA4 rearrangement in thyroid cancer
Papillary thyroid carcinoma. RET/NCOA4 may occur in non radiation-associated carcinomas but it is particularly common in radiation-associated tumors like those linked to the Chernobyl nuclear accident (1986).
RET/NCOA4 may be associated with aggressive behaviour. Among post-Chernobyl papillary carcinomas, RET/NCOA4 has been associated with tumors that were of shorter latency after radiation exposure, of larger size, with extrathyroidal extension, and that were classified as solid variant papillary carcinomas.
Simple karyotypes with balanced chromosomal inversions due to structural rearrangement of NCOA4 and RET gene on chromosome 10 [inv(10)(q11.2-q21)], resulting in RET/NCOA4.
Hybrid gene
Fusion protein
Atlas Image
Diagram of RET/NCOA4 oncogene. The red arrow indicates the breakpoint region.
RET/PTC oncogenes are generated by chromosomal rearrangements resulting in the fusion of the RET tyrosine-kinase (RET-TK) domain to the 5-terminal region of heterologous genes (e.g. H4, RIa, RFG5, hTIF1, RFG7, ELKS). All are balanced inversions or translocations which involve the 3.0 kb intron 11 of RET. RET-fused genes are widely expressed in human tissues, including thyroid follicular cells, and have putative dimerization domains. As the chimeric forms of RET-TK are translated into fusion proteins, these domains of the translocated amino terminal regions allow dimerization and thus ligand independent activation of RET-TK, which is considered essential for the transformation of thyroid cells. To date, at least 16 chimeric mRNAs involving 10 different genes have been reported, of which RET/PTC1 (consisting in the fusion of RET with H4) and RET/NCOA4 (consisting in the fusion of RET with NCOA4) are by far the most common.
ANIMAL MODELS RET/NCOA4 transgenic mice have been generated by Powell and coworkers using a construct with the RET/NCOA4 fusion gene downstream and under the control of the bovine thyroglobulin gene regulatory region; they express RET/NCOA4 selectively in the thyroid gland and develop thyroid hyperplasia and solid tumor variants of papillary carcinomas.


Pubmed IDLast YearTitleAuthors
98920171999Interaction of the putative androgen receptor-specific coactivator ARA70/ELE1alpha with multiple steroid receptors and identification of an internally deleted ELE1beta isoform.Alen P et al
156639892004Expression and function of androgen receptor coactivators in prostate cancer.Culig Z et al
103471671999Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma.Heinlein CA et al
167623192006Functional interaction of nuclear receptor coactivator 4 with aryl hydrocarbon receptor.Kollara A et al
96361571998Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells.Miyamoto H et al
181562102008Stimulation of prostate cancer cellular proliferation and invasion by the androgen receptor co-activator ARA70.Peng Y et al
98500891998The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids.Powell DJ Jr et al
107417392000Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications.Rabes HM et al
82902611994Molecular characterization of RET/PTC3; a novel rearranged version of the RETproto-oncogene in a human thyroid papillary carcinoma.Santoro M et al
174128012007Direct regulation of androgen receptor-associated protein 70 by thyroid hormone and its receptors.Tai PJ et al
117076262001RET oncogene activation in papillary thyroid carcinoma.Tallini G et al
86436071996Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells.Yeh S et al

Other Information

Locus ID:

NCBI: 8031
MIM: 601984
HGNC: 7671
Ensembl: ENSG00000266412


dbSNP: 8031
ClinVar: 8031
TCGA: ENSG00000266412


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Thyroid cancerKEGGko05216
Pathways in cancerKEGGhsa05200
Thyroid cancerKEGGhsa05216

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
246952232014Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy.221
253272882014Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo.154
272457392016Autophagy promotes ferroptosis by degradation of ferritin.120
163854512006A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.69
264362932015Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis.64
197306832009The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.59
210856292010Analysis of the 10q11 cancer risk locus implicates MSMB and NCOA4 in human prostate tumorigenesis.44
157720832005Endogenous coactivator ARA70 interacts with estrogen receptor alpha (ERalpha) and modulates the functional ERalpha/androgen receptor interplay in MCF-7 cells.31
186604892008Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations.26
128817132003Tyrosine kinase oncoprotein, RET/PTC3, induces the secretion of myeloid growth and chemotactic factors.23


Dario de Biase ; Luca Morandi ; Giovanni Tallini

NCOA4 (Nuclear Receptor Coactivator 4)

Atlas Genet Cytogenet Oncol Haematol. 2008-10-01

Online version: