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KCTD1 mutants in scalp-ear-nipple syndrome and AP-2? P59A in Char syndrome reciprocally abrogate their interactions, but can regulate Wnt/?-catenin signaling

ABSTRACT: Potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations are reported to result in scalp-ear-nipple syndrome. These mutations occur in the conserved broad-complex, tramtrack and bric a brac domain, which is associated with inhibited transcriptional activity. However, the mechanisms of KCTD1 mutants have not previously been elucidated; thus, the present study aimed to investigate whether KCTD1 mutants affect their interaction with transcription factor AP-2? and their regulation of the Wnt pathway. Results from the present study demonstrated that none of the ten KCTD1 mutants had an inhibitory effect on the transcriptional activity of AP-2?. Co-immunoprecipitation assays demonstrated that certain mutants exhibited changeable localization compared with the nuclear localization of wild-type KCTD1, but no KCTD1 mutant interacted with AP-2?. Almost all KCTD1 mutants, except KCTD1 A30E and H33Q, exhibited differential inhibitory effects on regulating TOPFLASH luciferase reporter activity. In addition, the interaction region of KCTD1 to the PY motif (amino acids 59–62) in AP-2? was identified. KCTD1 exhibited no suppressive effects on the transcriptional activity of the AP-2? P59A mutant, resulting in Char syndrome, a genetic disorder characterized by a distinctive facial appearance, heart defect and hand abnormalities, by altered protein cellular localization that abolished protein interactions. However, the P59A, P60A, P61R and 4A AP-2? mutants inhibited TOPFLASH reporter activity. Moreover, AP-2? and KCTD1 inhibited ?-catenin expression levels and SW480 cell viability. The present study thus identified a putative mechanism of disease-related KCTD1 mutants and AP-2? mutants by disrupting their interaction with the wildtype proteins AP-2? and KCTD1 and influencing the regulation of the Wnt/?-catenin pathway.

SUBMITTER: Hu L

PROVIDER: S-EPMC7533495 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Project description: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.

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KCTD1 mutants in scalp-ear-nipple syndrome and AP-2? P59A in Char syndrome reciprocally abrogate their interactions, but can regulate Wnt/?-catenin signaling

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