Abstract
The CDKN2B-AS1 gene, also called ANRIL, is located at the human CDKN2A/B locus at 9p21.3 and transcribed by RNA polymerase II into a long non-coding RNA of 3834 bp. The CDKN2B-AS1 gene overlaps a critical region of 125 kb covering the CDKN2B gene. The CDKN2A/B locus encompasses three major tumor suppressors juxtaposed and joined into a p16-CDKN2A/p15-CDKN2B/p14-ARF gene cluster. CDKN2A encodes splice variants p16-CDKN2A and p14-ARF, and CDKN2B encodes p15-CDKN2B. ANRIL shares a bidirectional promoter with the p14-ARF gene and is transcribed from the opposite strand to the cluster. We performed an analysis of the expression level of ANRIL and tumor suppressor p16-CDKN2A, p15-CDKN2B, and p14-ARF genes using quantitative RT-PCR in a multitumor panel. We observed the overexpression of the four genes ANRIL, p16-CDKN2A, p15-CDKN2B, and p14-ARF in the great majority of the 17 different cancer types. ANRIL was upregulated in 13/17 tumors compared to normal tissues, ranging from 5% (prostate cancer) to 91% (cervix cancer), with variable expression of p16-CDKN2A, p15-CDKN2B, and p14-ARF genes. A high positive correlation was identified between levels of expression of ANRIL and the three tumor suppressors. The strongest positive association was observed with p14-ARF (p < 0.001) in all but one (lung squamous cell carcinoma) of the examined tumor types. This correlation suggests coordinated deregulated mechanisms in all cancer types through aberrant activation of a bidirectional p14-ARF/ANRIL promoter. Furthermore, significant positive correlation was unexpectedly established in prostatic carcinomas, in contradiction with previous data.
Highlights
The CDKN2B-AS1 gene, called ANRIL, is located at the human CDKN2A/B locus at 9p21.3, and is transcribed by RNA polymerase II into a long non-coding RNA of 3834 bp
Against commonly accepted ANRIL- and PRC2/PRC1-induced epigenetic inactivation of the three oncosuppressors, positive correlations between ANRIL, p16-CDKN2A, and p15-CDKN2B genes were frequently identified in numerous tissues and non-cancerous diseases [24,25,26,27,28]
Most normal tissues showed non-significant association between the expression of ANRIL and genes belonging to the p16-CDKN2A/p15-CDKN2B/p14-ARF gene cluster, high positive correlations were identified between ANRIL and p16-CDKN2A, p15-CDKN2B, and p14-ARF genes in the great majority of malignant tumors, suggesting coordinated alterations of their regulation in all types of cancers
Summary
The CDKN2B-AS1 gene, called ANRIL, is located at the human CDKN2A/B locus at 9p21.3, and is transcribed by RNA polymerase II into a long non-coding RNA of 3834 bp. The PRC1 complex is composed of several subunits, such as PHC, CBX7, BMI1, and RING1a/1b, which catalyze the mono-ubiquitination of H2A on K119 (H2AK119ub1), so as to firmly maintain chromatin inactivation [10] During this process, ANRIL promotes specific interactions with the two proteins SUZ12 (PRC2) and CBX7 (PRC1), in order to stabilize PRC1/PRC2 complexes, modify the histone code of the p16-CDKN2A/p15-CDKN2B/p14-ARF locus, and ensure a firm and perennial transcriptional repression [5]. We identified an altered repressive function of PRC2 and PRC1 at RNA and protein levels, resulting in the absence of p16-CDKN2A/p15-CDKN2B/p14-ARF cluster inactivation with frequent p16-CDKN2A, p15-CDKN2B, and p14-ARF overexpressions This discrepancy between prostate and breast cancer suggests a large variability of the ANRIL/p16-CDKN2A/p15-CDKN2B/p14-ARF interaction network depending on the tumor type. SaSmamplpelsefsrofmrom d17iffderiffenetretynptetsyopfepsriomf aprryimtuamryortsu(mtotoarls, n(t=o7ta02l,; Snu=pp7l0em2;eSnutaprpylTemabelenSta1r)ywTeareble S1) owbtearieneodbftraoimnemd ufrltoim-cenmteurltDi-ecpeanrttemr eDnetspoafrtPmatehnotlsogoyf fPraotmho1l9o7g8ytofr2o0m10.1A97ll8ptaotie2n0t1s0w. eArellinpfaotrimenetds were thinaftotrhmeierdtutmhaotrtshaemirptluems morigshatmbpeleussemdifgohrtsbceieuntsiefidc fpourrspcoiesenst,ifiacndpuhrapdotshees,oapnpdorhtuadnitthyetoopdpecolrintuen. ity to Sdinecceli2n0e0.7S, ipnacteie2n0ts07tr,epaatetidenintsoturreaintesdtitiuntioounrs hinasvteitguitvioennsthheaivr eapgpivroenvatlhbeyirsaigpnperdovinaflobrmy esdigcnoendseinnfto. rmed Tchoins ssetnutd.yTfhoilsloswtueddyifnosltliotuwteiodnianlsgtiutuidteiolinnaelsgausidpeultinfoesrtahsbpyutthfeorFthrebnychthEethFirceanlcChoEmthmiciattleCe oamndmtihtteee and EtthheicEs tChiocms Cmoitmteme iotfteCeuorfieCuinrsiteitiuntseti(tAutgere(AemgreenetmneunmtbneurmCb7e5r-0C57-158-)0.5S-1a8m).pSleasmwpelrees wimemreeidmiamteelydiately stsotorerdedininliqliuqiudidnintriotrgoegnenunutinl tRilNRANeAxteraxctrtiaocntioanndanthdenthsetnorestdoraetd−8a0t −°C8.0A◦Ctu. mAotrusmamorplseamwpasle was bfacrcbfoeomronelomonlsimoncisdrcngioadecgtmnraeoetncreodenectrdaoenspsrnoutsa-paniucttta-aaiiiectctnbinaalecdnebtensiclrstfe(oeesodraurf(iososdsetutrhipasstitnahtshpatcaiineasetsttncw>uieste1dstan>ucys(tm1edsci.oygfc(fnem.rt,i.ofhfgmimerf.trm,ahopmtmeeumrdomamppmtbroouooyprmmrp)tlcaioofoooosprmrntrt)iliebawofossoinfnhtrfiiioteoncwurshfgmhbftaaorioucnemrrmhaibsocmaotrererlpmtmliashscusosoetenurllxtlopoeiscgshshe)seiioecsuoxdlatorecolesegcada)ehidncdoe7jaaamre0llcyd%aeaiscdnn.i7astjaN0alhnl%csyoaotesurs.rnmimdestNylanhaimloltaohrttsriiiamnmssetssalauuhatiemllaeedsststiiinssssauuteeedss reavmeailcerdoma Ketia6s7taintidcedxiosef aespeitthhealitawl caesllcsoonffi
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