Prognostic significance of AP-2α/γ targets as cancer therapeutics

Abstract

Identifying genes with prognostic importance could improve cancer treatment. An increasing number of reports suggest the existence of successful strategies based on seemingly “untargetable” transcription factors. In addition to embryogenesis, AP-2 transcription factors are known to play crucial roles in cancer development. Members of this family can be used as prognostic factors in oncological patients, and AP-2α/γ transcription factors were previously investigated in our pan-cancer comparative study using their target genes. The present study investigates tumors that were previously found similar with an emphasis on the possible role of AP-2 factors in specific cancer types. The RData workspace was loaded back to R environment and 3D trajectories were built via Monocle3. The genes that met the requirement of specificity were listed using top_markers(), separately for mutual and unique targets. Furthermore, the candidate genes had to meet the following requirements: correlation with AP-2 factor (through Correlation AnalyzeR) and validated prognostic importance (using GEPIA2 and subsequently KM-plotter or LOGpc). Eventually, the ROC analysis was applied to confirm their predictive value; co-dependence of expression was visualized via BoxPlotR. Some similar tumors were differentiated by AP-2α/γ targets with prognostic value. Requirements were met by only fifteen genes (EMX2, COL7A1, GRIA1, KRT1, KRT14, SLC12A5, SEZ6L, PTPRN, SCG5, DPP6, NTSR1, ARX, COL4A3, PPEF1 and TMEM59L); of these, the last four were excluded based on ROC curves. All the above genes were confronted with the literature, with an emphasis on the possible role played by AP-2 factors in specific cancers. Following ROC analysis, the genes were verified using immunohistochemistry data and progression-related signatures. Staining differences were observed, as well as co-dependence on the expression of e.g. CTNNB1, ERBB2, KRAS, SMAD4, EGFR or MKI67. In conclusion, prognostic value of targets suggested AP-2α/γ as candidates for novel cancer treatment. It was also revealed that AP-2 targets are related to tumor progression and that some mutual target genes could be inversely regulated.

Structural basis for specific DNA sequence motif recognition by the TFAP2 transcription factors

“…The TFAP2 family plays essential roles in regulating a variety of biological processes, and its dysfunction is associated with several human diseases and oncogenesis, such as BOFS, PDA, metastasis, lung carcinoma, carcinogenesis, and breast cancer ( 59 , 66–68 ). The TFAP2 family proteins are not only biomarkers for disease diagnosis but also important prognostic and therapeutic targets ( 14 , 69–71 ). Additionally, the 3D structure and DNA binding ability of the human TFAP2 is also conserved in Drosophila and C. elegans ( 72 , 73 ).…”

“…The TFAP2 proteins act as either transcriptional repressors or activators during differentiation, development, and organogenesis ( 5–12 ). In addition to their critical roles in normal biological functions, mutations and abnormal expression of the TFAP2 proteins have been linked to various diseases ( 13 , 14 ). Thus, the diverse functions of the TFAP2 transcription factors make them a promising area of research for both developmental biology and disease pathology.…”

Aberrant methylation of dipeptidyl peptidase‑like 6 as a potential prognostic biomarker for lung adenocarcinoma

“…Limited information is currently available on the oncogenic properties of the DPP6 gene. In patients with esophageal carcinoma, high expression levels of DPP6 were associated with shorter survival, and DPP6 was negatively regulated by activating enhancer-binding protein 2 (AP-2α) and positively by AP-2γ ( 27 ). Furthermore, in patients with esophageal squamous cell carcinoma, DPP6 was up-regulated by ARID3A and down-regulated by ZNF354C ( 28 ).…”

AP-2δ Is the Most Relevant Target of AP-2 Family-Focused Cancer Therapy and Affects Genome Organization

“…Typically, AP-2 transcription factors are expressed during embryogenesis and orchestrate the cell cycle, proliferation, and apoptosis, enabling appropriate development of, inter alia, limbs, eyes, or facial features [ 22 , 23 ]. Apart from our previous study that paved the way for AP-2α and AP-2γ to be considered as targeted therapy candidates [ 24 ], other authors [ 19 ] have put a different family member, AP-2δ, on the list of nearly three hundred oncogenic transcription factors and regulators, which could be a useful hint for TF-based cancer treatment. However, no studies were focused on the structural properties that would justify the rationale for targeting AP-2 proteins or could describe how to perform it selectively, without targeting other AP-2 family members.…”