678|NATURE|VOL555|29mARch2018LETTERdoi:10.1038/nature26140TheproteinhistidinephosphataseLHPPisatumoursuppressorSravanthK.hindupur1,marcocolombi1,StephenR.Fuhs2,matthiasS.matter3,YakirGuri1,KevinAdam2,marioncornu1,SalvatorePiscuoglio3,charlotteK.Y.Ng3,charlesBetz1,DritanLiko1,LucaQuagliata3,Suzettemoes1,PaulJenoe1,Luigim.Terracciano3,markush.heim4,Tonyhunter2&michaelN.hall1Histidinephosphorylation,theso-calledhiddenphosphoproteome,isapoorlycharacterizedpost-translationalmodificationofproteins1,2.Herewedescribearoleofhistidinephosphorylationintumorigenesis.Proteomicanalysisof12tumoursfromanmTOR-drivenhepatocellularcarcinomamousemodelrevealedthatNME1andNME2,theonlyknownmammalianhistidinekinases,wereupregulated.Conversely,expressionoftheputativehistidinephosphataseLHPPwasdownregulatedspecificallyinthetumours.WedemonstratethatLHPPisindeedaproteinhistidinephosphatase.Consistentwiththeseobservations,globalhistidinephosphorylationwassignificantlyupregulatedinthelivertumours.Sustained,hepaticexpressionofLHPPinthehepatocellularcarcinomamousemodelreducedtumourburdenandpreventedthelossofliverfunction.Finally,inpatientswithhepatocellularcarcinoma,lowexpressionofLHPPcorrelatedwithincreasedtumourseverityandreducedoverallsurvival.Thus,LHPPisaproteinhistidinephosphataseandtumoursuppressor,suggestingthatderegulatedhistidinephosphorylationisoncogenic.Livercanceristhesecondleadingcauseofcancer-relateddeathsglobally.Hepatocellularcarcinoma(HCC)representsapproximately90%ofprimarylivercancercases3.Recentstudiesindicatethatalmost50%ofHCCcasesdisplayaberrantPI3K–AKT–mTORsignalling4,includinglossofthetumoursuppressorsPTEN,TSC1,andTSC23(Fig.1a).WegeneratedanHCCmousemodelbyliver-specificdele-tionofPTENandTSC1,usingtheneonatallyexpressedalbuminpromoterasacredriver(seeMethods).Wehereafterrefertothismodelasliver-specificdouble-knockout(L-dKO)mice.L-dKOmiceinvariablyexhibitedhepatomegalyandadvancedlivertumoursat6and20weeksofage,respectively(Fig.1bandExtendedDataFig.1a).Histopathologicalanalys...
