Biology subjects

Sahu, V.

Publications and source records attributed to Sahu, V..

4 recordsLinked to original sources

bioRxiv2024

EPHA2 Regulates SOX2 during Esophageal Development

The human esophagus, derived from the anterior foregut endoderm, requires proper dorsal-ventral patterning for development. The transcription factor SOX2, crucial in this process, when dysregulated, leads to congenital esophageal abnormalities. EPHA2, a receptor tyrosine kinase, is vital in various developmental processes and cancer models, where it activates SOX2. This study demonstrates that EPHA2 regulates SOX2 expression during esophageal development using human iPSCs and iPSC-derived human esophageal organoids (HEO). Inhibition of EPHA2 decreased iPSC-derived HEO formation and SOX2 expression. These findings provide evidence of EPHA2 as being a key regulator of SOX2 signaling in early esophageal development. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/617209v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@16b8a8aorg.highwire.dtl.DTLVardef@1548672org.highwire.dtl.DTLVardef@46e28corg.highwire.dtl.DTLVardef@1c35578_HPS_FORMAT_FIGEXP M_FIG SFD: Serum-Free Differentiation media; EPC: esophageal progenitor cells; HEO: human esophageal organoids Created with BioRender.com C_FIG HighlightsO_LISOX2 is crucial for proper esophageal development. C_LIO_LIEPHA2 is a receptor tyrosine kinase involved in various developmental processes. C_LIO_LIEPHA2 activates SOX2. C_LIO_LIInhibition of EPHA2 decreased SOX2 expression and human esophageal organoid formation. C_LI

developmental biology↗

bioRxiv2024

Cancer-associated DNA Hypermethylation of Polycomb Targets Requires DNMT3A Dual Recognition of Histone H2AK119 Ubiquitination and the Nucleosome Acidic Patch

During tumor development, promoter CpG islands (CGIs) that are normally silenced by Polycomb repressive complexes (PRCs) become DNA hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) catalyze CpG methylation at PRC-regulated regions remains unclear. Here we report a cryo-EM structure of the DNMT3A long isoform (DNMT3A1) N-terminal region in complex with a nucleosome carrying PRC1-mediated histone H2A lysine 119 monoubiquitination (H2AK119Ub). We identify regions within the DNMT3A1 N-terminus that bind H2AK119Ub and the nucleosome acidic patch. This bidentate interaction is required for effective DNMT3A1 engagement with H2AK119Ub-modified chromatin in cells. Furthermore, aberrant redistribution of DNMT3A1 to Polycomb target genes inhibits their transcriptional activation during cell differentiation and recapitulates the cancer-associated DNA hypermethylation signature. This effect is rescued by disruption of the DNMT3A1-acidic patch interaction. Together, our analyses reveal a binding interface critical for countering promoter CGI DNA hypermethylation, a major molecular hallmark of cancer.

cancer biology↗

bioRxiv2022

Human papilloma virus E6 regulates therapy responses in oropharyngeal cancer by repressing the PGC-1α/ERRα axis

Therapy with radiation plus cisplatin kills human papilloma virus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) by increasing reactive oxygen species beyond cellular antioxidant capacity. To explore why some patients fail these standard treatments, we evaluated whether the variation in HPV oncoprotein levels among HPV+ OPSCCs impacts mitochondrial metabolism, a source of antioxidant capacity. In cell line and patient-derived xenograft models, levels of HPV full-length E6 (fl-E6) inversely correlated with oxidative phosphorylation, antioxidant capacity, and therapy resistance, and fl-E6 was the only HPV oncoprotein to display such correlation. Ectopically expressing fl-E6 in models with low levels reduced mitochondrial mass, depleted antioxidant capacity, and sensitized to therapy. In this setting, fl-E6 repressed the PGC-1/ERR pathway for mitochondrial biogenesis by reducing p53-dependent PGC-1 transcription. Concordant observations were made in three clinical cohorts, where expression of mitochondrial components was higher in tumors of patients with reduced survival. These tumors contained the lowest fl-E6 levels, highest p53 target gene expression, and an activated PGC-1/ERR pathway. Our findings demonstrate that E6 can potentiate treatment responses by depleting mitochondrial antioxidant capacity and provide evidence for low E6 negatively impacting patient survival. E6s interaction with the PGC-1/ERR axis has implications for predicting and targeting treatment resistance in OPSCC.

cancer biology↗

bioRxiv2019

Identifying predictors of HPV-related head and neck squamous cell carcinoma progression and survival through patient-derived models

Therapeutic innovation for human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is impaired by inadequate biomarkers and preclinical models. This study addressed both limitations using the largest panel of HPV+ HNSCC patient-derived xenografts (PDXs) and organoids described to date. Whole exome profiles of the PDXs were compared to those of HPV+ human tumors and cell lines, and genetic features of the models were analyzed relative to their growth properties and outcomes of their patients of origin. PDX engraftment enriched for negatively prognostic NOTCH1 mutations while preserving multiple features lost in existing cell lines, including PIK3CA mutations, TRAF3 deletion, and absence of EGFR amplification. Observation of more mutations in faster-growing models facilitated identification of an association between mutational burden and local progression in both HPV+ and HPV-HNSCCs. Reduced E7 and p16INK4A levels found in a PDX from a lethal case led to detection of a similar profile among recurrent HPV+ HNSCCs in two patient cohorts, where low E2F target gene expression downstream of E7 predicted recurrence and mortality. Our findings bridge a critical gap in preclinical models for HPV+ HNSCCs and simultaneously reveal novel applications for mutational burden and E2F target dysregulation in biomarker development.

cancer biology↗