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NACC1 (nucleus accumbens associated 1, BEN and BTB (POZ) domain containing)

Written2012-05Kai Lee Yap, Ie-Ming Shih
Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

(Note : for Links provided by Atlas : click)


Other aliasBEND8
LocusID (NCBI) 112939
Atlas_Id 44511
Location 19p13.2  [Link to chromosome band 19p13]
Location_base_pair Starts at and ends at bp from pter
Local_order Gene orientation: telomere-3' NACC1 5'-centromere.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
LAPTM4A (2p24.1) / NACC1 (19p13.2)


Description The NACC1 gene is encoded by 5 exons spanning 5958 base pairs that are located on chromosome 19p13.13.
Transcription 4556 bp linear mRNA. The coding sequence (1584 bp) is from 169-1752 bp.


Description NAC1 consists of 527 amino acids and the protein is predicted to have a molecular weight of 57258 Da (Stead et al., 2009). Comprising of a N terminal BTB/POZ domain and the C terminal BEN domain, NAC1 is missing a Zinc Finger domain unlike many members of the BTB/POZ family. The homodimerization of NAC1 mediated by the BTB domain is thought to be essential for its functional activities (Nakayama et al., 2006). The newly defined BEN domain may mediate protein-DNA interactions (Abhiman et al., 2008), however it remains to be investigated if NAC1 is indeed a DNA binding protein.
Expression Expressed in Arabidopsis root as a transcription activator, found in nuclear accumbens of neuronal tissues and overexpressed in various human neoplastic diseases (Cha et al., 1997; Xie et al., 2002; Guo et al., 2005; Nakayama et al., 2006; Shen et al., 2007; Nakayama et al., 2007; Yeasmin et al., 2008; Mackler et al., 2008; Ishibashi et al., 2009; Korutla et al., 2009; Ishikawa et al., 2010; Yeasmin et al., 2011).
Localisation Nucleus and cytoplasm. Dynamic changes in subcellular localization of NAC1 at the different phases of cell cycle progression were documented. In non-mitotic cells, NAC1 accumulated in distinct nuclear punctate bodies. During mitosis, these punctate nuclear bodies dissolve into a diffuse pattern of distribution in the cytoplasm. NAC1 nuclear bodies reappeared once mitosis was completed and the nuclear membrane reformed. (Wu et al., 2011).
Function First identified as a novel transcript in the nucleus-accumbens of cocaine-addicted rats (Cha et al., 1997), NAC1 was known as a transcriptional corepressor (Korutla et al., 2009) with well defined functions in the murine neurologic physiological pathways (Shen et al., 2007; Mackler et al., 2008) and Arabidopsis root development (Xie et al., 2002; Guo et al., 2005). The role of NAC1 in human cancer was unknown. Preliminary studies of SAGE (Serial Analysis of Gene Expression) libraries were conducted to elucidate the role of NAC1 in the pathogenesis of human cancers and had revealed the higher expression levels of NAC1 in tumor samples as compared to the normal tissues in various cancer types such as pancreas, liver, and breast (Nakayama et al., 2006). Following that, detailed gene expression studies were undertaken in patient tumor samples and characterized the overexpression of NAC1 in cervical carcinoma and ovarian high-grade serous carcinoma, one of the most lethal neoplastic diseases in women (Nakayama et al., 2006; Nakayama et al., 2007; Yeasmin et al., 2008; Ishibashi et al., 2009; Jinawath et al., 2009; Nakayama et al., 2010; Ishikawa et al., 2010; Shih et al., 2011; Yeasmin et al., 2011). Amplification of NACC1 has also been recently reported in ovarian cancer, and analysis of The Cancer Genome Atlas data set revealed that NACC1 was one of the top potential "driver" genes that showed the highest correlation between DNA and RNA copy number in ovarian high-grade serous carcinomas (Shih et al., 2011). Additionally, NAC1 up-regulation is associated with disease aggressiveness and contributes to the development of chemo-resistance (Nakayama et al., 2006; Jinawath et al., 2009; Nakayama et al., 2010; Zhang et al., 2012). NAC1 enables the survival and growth of ovarian cancer cells by regulating several downstream targets including those involved in Gadd45 cell survival pathway (Nakayama et al., 2007; Jinawath et al., 2009), fatty acid metabolism (Ueda et al., 2010), and HMGB-1 mediated autophagic response (Zhang et al., 2012). NAC1 function has also been demonstrated to be essential for the migration of ovarian and melanoma cancer cells (Yamazaki et al., 2005; Nakayama et al., 2010). Mouse tumor xenograft studies illustrated the in vivo therapeutic potential of inactivating Nac1 function; as such manipulation in SKOV3 ovarian cancer cells and HeLa cervical cancer cells was demonstrated to be sufficient to inhibit the growth of tumor xenografts (Nakayama et al., 2006). Nac1 is more recently associated with maintenance of the pluripotency of mouse embryonic stem cells through its interaction with Nanog (Wang et al., 2006; Ma et al., 2009).
  Functions of NAC1 in various systems and pathways.
Homology BEN1 domain, BTB/POZ domain.

Implicated in

Entity Ovarian serous carcinoma
Disease NACC1 is highly overexpressed in ovarian carcinomas. High NAC1 expression is correlated with early tumor recurrence (Nakayama et al., 2006). Nakayama et al. found there is significant correlation between poor prognosis and the expression of NAC1 in patients who received taxol therapy. In addition, high immunoreactivity to NAC1 in the primary ovarian tumor is able to predict early tumor recurrence. The mechanism of over expression of NAC1 in ovarian serous carcinoma is by amplication of the gene locus ch19p13.2 carrying the NACC1 gene (Shih et al., 2011). NAC1 function is important for the survival and proliferation of ovarian cancer cells, and increases their migration and motility (Nakayama et al., 2010). Zhang et al. found that NAC1 is also implicated in autophagic response in the ovarian cancer cell line, which may contribute to the development of chemoresistance (Zhang et al., 2012).
Entity Cervical carcinomas
Disease Using immunohistochemistry, Yeasmin et al. found that NACC1 is more frequently overexpressed in cervical adenocarcinomas and adenosquamous carcinomas as compared to squamous cell carcinomas (Yeasmin et al., 2008). In squamous cell carcinomas that have overexpression of NAC1, NACC1 gene amplication was detected, and positive NAC1 expression is linked to shorter overall survival. NAC1-silenced cancer cells undergo growth inhibition, increased apoptosis, decreased proliferation, cellular migration and invasion.
Entity Endometrial carcinomas
Disease NAC1 was found to be overexpressed in the normal endometrium in the early and mid proliferative phases by the actions of circulating estrogen (Ishibashi et al., 2009). Ishikawa et al. found that there were significant correlations between positive NAC1 expression and pathological grade in endometrial carcinomas (Ishikawa et al., 2010). Endometrial carcinomas with NAC1 overexpression were found to be clinically aggressive, high-grade carcinomas. However unexpectedly they also found that during the progression from normal endometrium to hyperplasia and finally to carcinoma, there is a stepwise reduction in NAC1 protein expression. It was proposed that this might be related to loss of estrogen signaling in development of endometrial cancers (Ishibashi et al., 2009).


BEN: a novel domain in chromatin factors and DNA viral proteins.
Abhiman S, Iyer LM, Aravind L.
Bioinformatics. 2008 Feb 15;24(4):458-61. Epub 2008 Jan 18.
PMID 18203771
NAC-1, a rat brain mRNA, is increased in the nucleus accumbens three weeks after chronic cocaine self-administration.
Cha XY, Pierce RC, Kalivas PW, Mackler SA.
J Neurosci. 1997 Sep 15;17(18):6864-71.
PMID 9278521
MicroRNA directs mRNA cleavage of the transcription factor NAC1 to downregulate auxin signals for arabidopsis lateral root development.
Guo HS, Xie Q, Fei JF, Chua NH.
Plant Cell. 2005 May;17(5):1376-86. Epub 2005 Apr 13.
PMID 15829603
Expression of a BTB/POZ protein, NAC1, is essential for the proliferation of normal cyclic endometrial glandular cells and is up-regulated by estrogen.
Ishibashi M, Nakayama K, Yeasmin S, Katagiri A, Iida K, Nakayama N, Miyazaki K.
Clin Cancer Res. 2009 Feb 1;15(3):804-11.
PMID 19188150
NAC1, a potential stem cell pluripotency factor expression in normal endometrium, endometrial hyperplasia and endometrial carcinoma.
Ishikawa M, Nakayama K, Yeasmin S, Katagiri A, Iida K, Nakayama N, Miyazaki K.
Int J Oncol. 2010 May;36(5):1097-103.
PMID 20372782
NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathway.
Jinawath N, Vasoontara C, Yap KL, Thiaville MM, Nakayama K, Wang TL, Shih IM.
Oncogene. 2009 May 7;28(18):1941-8. Epub 2009 Mar 23.
PMID 19305429
NAC1, a POZ/BTB protein that functions as a corepressor.
Korutla L, Wang P, Jackson TG, Mackler SA.
Neurochem Int. 2009 Mar-Apr;54(3-4):245-52. Epub 2008 Dec 13.
PMID 19121354
The C-terminal pentapeptide of Nanog tryptophan repeat domain interacts with Nac1 and regulates stem cell proliferation but not pluripotency.
Ma T, Wang Z, Guo Y, Pei D.
J Biol Chem. 2009 Jun 12;284(24):16071-81. Epub 2009 Apr 14.
PMID 19366700
Requirement for the POZ/BTB protein NAC1 in acute but not chronic psychomotor stimulant response.
Mackler S, Pacchioni A, Degnan R, Homan Y, Conti AC, Kalivas P, Blendy JA.
Behav Brain Res. 2008 Feb 11;187(1):48-55. Epub 2007 Sep 2.
PMID 17945361
Biological role and prognostic significance of NAC1 in ovarian cancer.
Nakayama K, Rahman MT, Rahman M, Yeasmin S, Ishikawa M, Katagiri A, Iida K, Nakayama N, Miyazaki K.
Gynecol Oncol. 2010 Dec;119(3):469-78. Epub 2010 Sep 24.
PMID 20869761
NAC1 regulates the recruitment of the proteasome complex into dendritic spines.
Shen H, Korutla L, Champtiaux N, Toda S, LaLumiere R, Vallone J, Klugmann M, Blendy JA, Mackler SA, Kalivas PW.
J Neurosci. 2007 Aug 15;27(33):8903-13.
PMID 17699672
Amplification of the ch19p13.2 NACC1 locus in ovarian high-grade serous carcinoma.
Shih IeM, Nakayama K, Wu G, Nakayama N, Zhang J, Wang TL.
Mod Pathol. 2011 May;24(5):638-45. Epub 2011 Jan 14.
PMID 21240255
Structure of the human Nac1 POZ domain.
Stead MA, Carr SB, Wright SC.
Acta Crystallogr Sect F Struct Biol Cryst Commun. 2009 May 1;65(Pt 5):445-9. Epub 2009 Apr 24.
PMID 19407373
Expression of Fatty Acid Synthase Depends on NAC1 and Is Associated with Recurrent Ovarian Serous Carcinomas.
Ueda SM, Yap KL, Davidson B, Tian Y, Murthy V, Wang TL, Visvanathan K, Kuhajda FP, Bristow RE, Zhang H, Shih IeM.
J Oncol. 2010;2010:285191. Epub 2010 May 19.
PMID 20508725
A protein interaction network for pluripotency of embryonic stem cells.
Wang J, Rao S, Chu J, Shen X, Levasseur DN, Theunissen TW, Orkin SH.
Nature. 2006 Nov 16;444(7117):364-8. Epub 2006 Nov 8.
PMID 17093407
Cell cycle-dependent alteration in NAC1 nuclear body dynamics and morphology.
Wu PH, Hung SH, Ren T, Shih IeM, Tseng Y.
Phys Biol. 2011 Feb;8(1):015005. Epub 2011 Feb 7.
PMID 21301057
SINAT5 promotes ubiquitin-related degradation of NAC1 to attenuate auxin signals.
Xie Q, Guo HS, Dallman G, Fang S, Weissman AM, Chua NH.
Nature. 2002 Sep 12;419(6903):167-70.
PMID 12226665
Regulation of cancer cell motility through actin reorganization.
Yamazaki D, Kurisu S, Takenawa T.
Cancer Sci. 2005 Jul;96(7):379-86.
PMID 16053508
Biological and clinical significance of NAC1 expression in cervical carcinomas: a comparative study between squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas.
Yeasmin S, Nakayama K, Rahman MT, Rahman M, Ishikawa M, Katagiri A, Iida K, Nakayama N, Otuski Y, Kobayashi H, Nakayama S, Miyazaki K.
Hum Pathol. 2012 Apr;43(4):506-19. Epub 2011 Sep 1.
PMID 21889186
NAC1 modulates sensitivity of ovarian cancer cells to cisplatin by altering the HMGB1-mediated autophagic response.
Zhang Y, Cheng Y, Ren X, Zhang L, Yap KL, Wu H, Patel R, Liu D, Qin ZH, Shih IM, Yang JM.
Oncogene. 2012 Feb 23;31(8):1055-64. doi: 10.1038/onc.2011.290. Epub 2011 Jul 11.
PMID 21743489


This paper should be referenced as such :
Yap, KL ; Shih, IM
NACC1 (nucleus accumbens associated 1, BEN, BTB (POZ) domain containing)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(10):723-726.
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External links

Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)112939
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
canSAR (ICR) (select the gene name)
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