RESUMO
Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily involves the cardiovascular and respiratory systems, neurological manifestations, including movement disorders such as myoclonus and cerebellar ataxia, have also been reported. However, the occurrence of post-SARS-CoV-2 chorea is rare. Herein, we describe a 91-year-old female with a past medical history of hypothyroidism who developed chorea after two weeks of contracting a mild coronavirus disease (COVID-19).
RESUMO
In melanoma metastasis, the role of the AP-2α transcription factor, which is encoded by TFAP2A, is controversial as some findings have suggested tumor suppressor activity while other studies have shown high TFAP2A expression in node-positive melanoma associated with poor prognosis. Here we demonstrate that AP-2α facilitates melanoma metastasis through transcriptional activation of genes within the E2F pathway including EZH2. A BioID screen found that AP-2α interacts with members of the nucleosome remodeling and deacetylase (NuRD) complex. Loss of AP-2α removed activating chromatin marks in the promoters of EZH2 and other E2F target genes through activation of the NuRD repression complex. In melanoma cells, treatment with tazemetostat, an FDA-approved and highly specific EZH2 inhibitor, substantially reduced anchorage-independent colony formation and demonstrated heritable antimetastatic effects, which were dependent on AP-2α. Single-cell RNA sequencing analysis of a metastatic melanoma mouse model revealed hyperexpansion of Tfap2a High/E2F-activated cell populations in transformed melanoma relative to progenitor melanocyte stem cells. These findings demonstrate that melanoma metastasis is driven by the AP-2α/EZH2 pathway and suggest that AP-2α expression can be used as a biomarker to predict responsiveness to EZH2 inhibitors for the treatment of advanced melanomas. SIGNIFICANCE: AP-2α drives melanoma metastasis by upregulating E2F pathway genes including EZH2 through inhibition of the NuRD repression complex, serving as a biomarker to predict responsiveness to EZH2 inhibitors.
Assuntos
Complexo 2 de Proteínas Adaptadoras/metabolismo , Subunidades alfa do Complexo de Proteínas Adaptadoras/metabolismo , Fatores de Transcrição E2F/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Melanoma/metabolismo , Animais , Sequência de Bases , Benzamidas/farmacologia , Biomarcadores/metabolismo , Compostos de Bifenilo/farmacologia , Linhagem Celular Tumoral , Epigênese Genética , Humanos , Melanócitos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Morfolinas/farmacologia , Metástase Neoplásica , Transplante de Neoplasias , Segunda Neoplasia Primária , Regiões Promotoras Genéticas , Piridonas/farmacologia , Análise de Célula Única , Fator de Transcrição AP-2RESUMO
The expression of carbonic anhydrase XII (CA12) is associated with the expression of estrogen receptor alpha (ERα) in breast cancer and is linked to a good prognosis with a lower risk of metastasis. Transcription Factor Activator Protein 2γ (TFAP2C, AP-2γ) governs luminal breast cancer phenotype through direct and indirect regulation of ERα and ERα-associated genes, GATA3, FOXA1, EGFR, CDH1, DSP, KRT7, FBP1, MYB, RET, KRT8, MUC1, and ERBB2-genes which are responsible for the luminal signature in breast cancer. Herein, utilizing chromatin immunoprecipitation and direct sequencing (ChIP-seq), we show that CA12 is regulated by AP-2γ through binding with its promoter region in luminal breast cancer cell lines and indirectly through a distal estrogen-responsive region in ERα-positive cell lines by upregulation of ERα. CA12 is transcriptionally silenced in basal breast cancer cell lines through histone deacetylation and CpG methylation of the promoter region and can be re-activated with Trichostatin A (histone deacetylase inhibitor) and/or 5-aza-dC (an inhibitor of DNA methylation). Strong concordance in co-expression of CA12 and ESR1 (R2 = 0.1128, p = 0486) and TFAP2C (R2 = 0.1823, p = 0.0105) was found using a panel of primary breast tumor samples (n = 35), supporting a synergetic role of AP-2γ and ERα in activation of CA12. Our results highlight the essential role of AP-2γ in maintaining the luminal breast cancer phenotype and provide evidence that epigenetic mechanisms silence luminal gene expression in the basal phenotype. Additional studies to decipher mechanisms that drive epigenetic silencing of AP-2γ target genes are a critical area for further research.