2024
ZNF397 Deficiency Triggers TET2-driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer
Xu Y, Yang Y, Wang Z, Sjostrom M, Jiang Y, Tang Y, Cheng S, Deng S, Wang C, Gonzalez J, Johnson N, Li X, Li X, Metang L, Mukherji A, Xu Q, Tirado C, Wainwright G, Yu X, Barnes S, Hofstad M, Chen Y, Zhu H, Hanker A, Raj G, Zhu G, He H, Wang Z, Arteaga C, Liang H, Feng F, Wang Y, Wang T, Mu P. ZNF397 Deficiency Triggers TET2-driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer. Cancer Discovery 2024, 14: 1496-1521. PMID: 38591846, PMCID: PMC11285331, DOI: 10.1158/2159-8290.cd-23-0539.Peer-Reviewed Original ResearchConceptsLineage plasticityTherapy resistanceProstate cancerCancer cellsAndrogen receptorResistance to AR-targeted therapiesLuminal lineageAR-targeted therapiesOvercome therapy resistanceTransition of cancer cellsEpigenetic regulatory machineryBona fide coactivatorTherapy responseAR signalingEpigenetic rewiringDrug resistanceTherapeutic strategiesEpigenetic reprogrammingProstateTherapyCancerPhenotypic plasticityRegulatory machineryAndrogenTranscriptional programs
2023
UBE2J1 is the E2 ubiquitin-conjugating enzyme regulating androgen receptor degradation and antiandrogen resistance
Rodriguez Tirado C, Wang C, Li X, Deng S, Gonzalez J, Johnson N, Xu Y, Metang L, Sundar Rajan M, Yang Y, Yin Y, Hofstad M, Raj G, Zhang S, Lemoff A, He W, Fan J, Wang Y, Wang T, Mu P. UBE2J1 is the E2 ubiquitin-conjugating enzyme regulating androgen receptor degradation and antiandrogen resistance. Oncogene 2023, 43: 265-280. PMID: 38030789, PMCID: PMC10798893, DOI: 10.1038/s41388-023-02890-5.Peer-Reviewed Original ResearchConceptsAberrant androgen receptorProstate cancerAR ubiquitinationAR degradationAntiandrogen therapyResistance to antiandrogen therapyE2 ubiquitin-conjugating enzymeEnhanced AR signalingAndrogen receptor degradersAR protein levelsProstate cancer patientsUbiquitin-conjugating enzymeResistant tumorsPCa tumorsAR signalingAndrogen receptorAntiandrogen treatmentAntiandrogen resistanceAR proteinReceptor degradationProtein levelsOncogenic proteinsTumorTherapyProtein degradation processThe Critical Interplay of CAF Plasticity and Resistance in Prostate Cancer.
Li X, Mu P. The Critical Interplay of CAF Plasticity and Resistance in Prostate Cancer. Cancer Research 2023, 83: 2990-2992. PMID: 37504898, DOI: 10.1158/0008-5472.can-23-2260.Commentaries, Editorials and LettersConceptsCastration-resistant prostate cancerAndrogen deprivation therapyProstate cancerAndrogen receptorCastration-resistant prostate cancer developmentDevelopment of castration-resistant prostate cancerGenetically engineered mouse modelsMyofibroblastic cancer-associated fibroblastsOvercome treatment resistanceCancer-associated fibroblastsIncreased tumor heterogeneityDeprivation therapyCRPC developmentProstate tumorsTumor microenvironmentLineage plasticityTreatment resistanceStromal compartmentStandard treatmentTumor heterogeneityCancer recurrenceDrug resistanceDisease progressionMouse modelSingle-cell RNA sequencingLoss of SYNCRIP unleashes APOBEC-driven mutagenesis, tumor heterogeneity, and AR-targeted therapy resistance in prostate cancer
Li X, Wang Y, Deng S, Zhu G, Wang C, Johnson N, Zhang Z, Tirado C, Xu Y, Metang L, Gonzalez J, Mukherji A, Ye J, Yang Y, Peng W, Tang Y, Hofstad M, Xie Z, Yoon H, Chen L, Liu X, Chen S, Zhu H, Strand D, Liang H, Raj G, He H, Mendell J, Li B, Wang T, Mu P. Loss of SYNCRIP unleashes APOBEC-driven mutagenesis, tumor heterogeneity, and AR-targeted therapy resistance in prostate cancer. Cancer Cell 2023, 41: 1427-1449.e12. PMID: 37478850, PMCID: PMC10530398, DOI: 10.1016/j.ccell.2023.06.010.Peer-Reviewed Original ResearchConceptsProstate cancerTherapy resistanceTumor heterogeneityTumor mutational burdenCell-intrinsic mechanismsPromote tumor heterogeneityMutational burdenTargeted therapyDriver mutationsPCa cellsCancer cellsHuman cancersMutated genesCancerMutational signaturesProstateTumorTherapyFOXA1APOBEC proteinsAPOBEC3BEP300Molecular brakeMutationsSYNCRIP
2022
Ectopic JAK–STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance
Deng S, Wang C, Wang Y, Xu Y, Li X, Johnson N, Mukherji A, Lo U, Xu L, Gonzalez J, Metang L, Ye J, Tirado C, Rodarte K, Zhou Y, Xie Z, Arana C, Annamalai V, Liu X, Vander Griend D, Strand D, Hsieh J, Li B, Raj G, Wang T, Mu P. Ectopic JAK–STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance. Nature Cancer 2022, 3: 1071-1087. PMID: 36065066, PMCID: PMC9499870, DOI: 10.1038/s43018-022-00431-9.Peer-Reviewed Original ResearchConceptsJAK-STAT activationJanus kinase (JAK)-signal transducerTherapy resistanceLineage plasticityTranscriptional programsJAK-STATAR-targeted therapiesLineage programsLineagesMolecular mechanismsTranscriptomic aberrationsPharmaceutical inhibitionProstate cancerTargeted therapyStem-likeTherapeutic targetTherapy
2020
Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation
Zhang Z, Zhou C, Li X, Barnes S, Deng S, Hoover E, Chen C, Lee Y, Zhang Y, Wang C, Metang L, Wu C, Tirado C, Johnson N, Wongvipat J, Navrazhina K, Cao Z, Choi D, Huang C, Linton E, Chen X, Liang Y, Mason C, de Stanchina E, Abida W, Lujambio A, Li S, Lowe S, Mendell J, Malladi V, Sawyers C, Mu P. Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation. Cancer Cell 2020, 37: 584-598.e11. PMID: 32220301, PMCID: PMC7292228, DOI: 10.1016/j.ccell.2020.03.001.Peer-Reviewed Original ResearchMeSH KeywordsAndrogen AntagonistsAnimalsApoptosisBiomarkers, TumorCell ProliferationChromatinDNA HelicasesDNA-Binding ProteinsDrug Resistance, NeoplasmGene Expression Regulation, NeoplasticHigh-Throughput Screening AssaysHumansMaleMiceProstatic Neoplasms, Castration-ResistantReceptors, AndrogenRNA, Small InterferingTranscription FactorsTumor Cells, CulturedXenograft Model Antitumor AssaysConceptsAntiandrogen resistanceChromatin dysregulationCHD1 lossProstate cancerGenomic copy number alterationsRNA-seq analysisResistance to hormonal therapyCopy number alterationsAR-targeted therapiesMetastatic prostate cancerATAC-seqClosed chromatinRNA-seqTranscriptional plasticityTranscription factorsFunctional screeningTranscriptomic changesMechanisms of resistanceHormone therapyLineage programsChromatinCHD1Global changeIntegrated analysisTherapy