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Transcription factor ZNF263 enhances EGFR-targeted therapeutic response and reduces residual disease in lung adenocarcinoma [RNAseq2]

ABSTRACT: EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) have achieved clinical successes in lung adenocarcinoma (LUAD). However, tumors often show profound but transient initial response and gain resistance. Here, we identified transcription factor ZNF263 as being significantly decreased in osimertinib-resistant or drug-tolerant persister LUAD cells and clinical residual tumor specimens. Exogenous expression of ZNF263 improved the initial response of cells and delayed the formation of persister cells with osimertinib. We elaborated that ZNF263 bound and recruited DNMT1 to the EGFR gene promoter, suppressing EGFR transcription with DNA hypermethylation. ZNF263 could also interact with nuclear EGFR (nEGFR), impairing the nEGFR-STAT5 interaction to enhance AURKA expression. Overexpressing ZNF263 also made tumor cells with wild-type EGFR expression or refractory EGFR mutations more susceptible to EGFR inhibition. More importantly, lentivirus or AAV-mediated plasmid delivery of ZNF263 synergistically suppressed tumor growth and regrowth with osimertinib in xenograft animal models. These findings suggest that enhancing ZNF263 may achieve complete response in LUAD with EGFR-targeted therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253742 | GEO | 2024/01/23

REPOSITORIES: GEO

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Transcription factor ZNF263 enhances EGFR-targeted therapeutic response and reduces residual disease in lung adenocarcinoma [RNAseq]

Project description:EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) have achieved clinical successes in lung adenocarcinoma (LUAD). However, tumors often show profound but transient initial response and gain resistance. Here, we identified transcription factor ZNF263 as being significantly decreased in osimertinib-resistant or drug-tolerant persister LUAD cells and clinical residual tumor specimens. Exogenous expression of ZNF263 improved the initial response of cells and delayed the formation of persister cells with osimertinib. We elaborated that ZNF263 bound and recruited DNMT1 to the EGFR gene promoter, suppressing EGFR transcription with DNA hypermethylation. ZNF263 could also interact with nuclear EGFR (nEGFR), impairing the nEGFR-STAT5 interaction to enhance AURKA expression. Overexpressing ZNF263 also made tumor cells with wild-type EGFR expression or refractory EGFR mutations more susceptible to EGFR inhibition. More importantly, lentivirus or AAV-mediated plasmid delivery of ZNF263 synergistically suppressed tumor growth and regrowth with osimertinib in xenograft animal models. These findings suggest that enhancing ZNF263 may achieve complete response in LUAD with EGFR-targeted therapies.

2024-01-23 | GSE253741 | GEO

Transcription factor ZNF263 enhances EGFR-targeted therapeutic response and reduces residual disease in lung adenocarcinoma [ChIP-seq]

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Project description:Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or EGFR T790M resistance mutations. Whilst patients treated with osimertinib show clinical benefit, disease progression and drug resistance are common. Emergence of de novo acquired resistance from a drug tolerant persister (DTP) cell population is one mechanism proposed to explain progression on osimertinib and other targeted cancer therapies. Here we profiled osimertinib DTPs using RNA-seq, ChIP-seq, and ATAC-seq to characterize the features of these cells and performed drug screens to identify therapeutic opportunities.

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Genomic targets of the KRAB and scan domain-containing zinc finger protein 263 (ZNF263).

Project description:Half of all human transcription factors use C2H2 zinc finger domains to specify site-specific DNA binding and yet very little is known about their role in gene regulation. Based on in vitro studies, a zinc finger code has been developed that predicts a binding motif for a particular zinc finger factor (ZNF). However, very few studies have performed genome-wide analyses of ZNF binding patterns and thus it is not clear if the binding code developed in vitro will be useful for identifying target genes of a particular ZNF. We performed genome-wide ChIP-seq for ZNF263, a C2H2 ZNF that contains 9 finger domains, a KRAB repression domain, and a SCAN domain and identified more than 5000 binding sites in K562 cells. Our results suggest that ZNF263 binds to a 24 nt site which differs from the motif predicted by the zinc finger code in several positions. Interestingly, many of the ZNF263 binding sites are located within the transcribed region of the target gene. Although ZNFs containing a KRAB domain are thought to function mainly as transcriptional repressors, many of the ZNF263 target genes are expressed at high levels. To address the biological role of ZNF263, we identified genes whose expression was altered by treatment of cells with ZNF263-specific siRNAs. Our results suggest that ZNF263 can have both positive and negative effects on transcriptional regulation of its target genes. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf Examination of ZNF263 ChIP-seq in K562 cells.

2009-12-03 | E-GEOD-19235 | biostudies-arrayexpress

Genomic targets of the KRAB and scan domain-containing zinc finger protein 263 (ZNF263).

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Project description:Oncogenic mutations in the EGFR gene account for 15-20% of lung adenocarcinoma (LUAD) cases. However, the mechanism for EGFR driven tumor development and growth is not fully understood. Here, using a mRNA expression profiling-based approach we identified betacellulin (BTC) as one the gene upregulated by oncogenic EGFR in a MAP kinase-dependent manner. BTC protein expression was markedly increased in LUAD patient samples compared to normal lung tissue, with higher expression in EGFR-mutant LUAD. BTC was sufficient to transform immortalized mouse cells, initiate tumor development in mice, and promote the survival of immortalized human lung epithelial cells. Conversely, knockdown of BTC inhibited the growth of EGFR-mutant human LUAD cells in culture and their tumor-forming ability in mice. Mechanistically, BTC knockdown resulted in attenuated EGFR signaling and apoptosis induction. Collectively, these results demonstrate a key role of BTC in EGFR-mutant LUAD, with potential therapeutic implications in LUAD and other EGFR-mutant cancers.

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