Molecular Analysis of ZNF71 KRAB in Non-Small-Cell Lung Cancer

Abstract

Our previous study found that zinc finger protein 71 (ZNF71) mRNA expression was associated with chemosensitivity and its protein expression was prognostic of non-small-cell lung cancer (NSCLC). The Krüppel associated box (KRAB) transcriptional repression domain is commonly present in human zinc finger proteins, which are linked to imprinting, silencing of repetitive elements, proliferation, apoptosis, and cancer. This study revealed that ZNF71 KRAB had a significantly higher expression than the ZNF71 KRAB-less isoform in NSCLC tumors (n = 197) and cell lines (n = 117). Patients with higher ZNF71 KRAB expression had a significantly worse survival outcome than patients with lower ZNF71 KRAB expression (log-rank p = 0.04; hazard ratio (HR): 1.686 [1.026, 2.771]), whereas ZNF71 overall and KRAB-less expression levels were not prognostic in the same patient cohort. ZNF71 KRAB expression was associated with epithelial-to-mesenchymal transition (EMT) in both patient tumors and cell lines. ZNF71 KRAB was overexpressed in NSCLC cell lines resistant to docetaxel and paclitaxel treatment compared to chemo-sensitive cell lines, consistent with its association with poor prognosis in patients. Therefore, ZNF71 KRAB isoform is a more effective prognostic factor than ZNF71 overall and KRAB-less expression for NSCLC. Functional analysis using CRISPR-Cas9 and RNA interference (RNAi) screening data indicated that a knockdown/knockout of ZNF71 did not significantly affect NSCLC cell proliferation in vitro.

Identification of Prognostic and Chemopredictive microRNAs for Non-Small-Cell Lung Cancer by Integrating SEER-Medicare Data

“…A recent meta-analysis showed that gefitinib and erlotinib have comparable effects on patient survival, overall response rate, and disease control rate, with no considerable variation with regard to EGFR mutation status, ethnicity, line of treatment, and baseline brain metastasis status [ 33 ]. EGFR mutation in the studied NSCLC cell lines was provided in our previous study [ 34 ].…”

A Multi-Omics Network of a Seven-Gene Prognostic Signature for Non-Small Cell Lung Cancer

“…Emerging evidence links epithelial to mesenchymal transition (EMT) to tumor progression, metastasis, and resistance to cancer therapy [ 15 , 16 , 17 , 18 ]. We reported that ZNF71 KRAB isoform was associated with EMT in NSCLC tumors and cell lines [ 19 ].…”

“…TRIM28 contributes to EMT and might be involved in lung cancer metastasis [ 25 ]. We previously reported that ZNF71 KRAB was associated with EMT and patient outcomes [ 19 ]. Nevertheless, the function of ZNF71 KRAB in EMT is not known.…”

“…The gene expression of these proliferation networks was further analyzed with L1000 Connectivity Map (CMap) [ 26 , 27 ] to identify matched functional pathways in shRNA knockdown, CRISPR-Cas9 knockout, or overexpression assays in NSCLC cell lines. Finally, the 14-gene EMT classifier constructed in our previous study for characterizing NSCLC tumor EMT states [ 19 ] was combined with the identified multi-omics network of the seven-gene signature to generate mechanistic hypotheses and discover repositioning drugs to reverse EMT, to enhance drug sensitivity, and to inhibit ICIs and NSCLC proliferation. Such a revelation will provide insight for designing therapeutic strategies for NSCLC intervention in future research.…”

Immune-Omics Networks of CD27, PD1, and PDL1 in Non-Small Cell Lung Cancer

“…Included in this 7-gene assay, CD27 and ZNF71 had concordant mRNA and protein expression in NSCLC tumors [12]. Our recent study showed that ZNF71-KRAB, the KRAB isoform that is transcriptional repression, was associated with EMT in NSCLC tumors and cell lines [119]. CD27, an emerging ICI [13], is being tested as adjuvant therapy in phase I/II clinical trials for multiple tumor types with promising results [14,15].…”