Biology subjects

Abatti, L. E.

Publications and source records attributed to Abatti, L. E..

3 recordsLinked to original sources

bioRxiv2024

Transcriptional repression of SOX2 by p53 in cancer cells regulates cell identity and migration

During cancer development and progression, many genetic alterations lead to the acquisition of novel features that confer selective advantage to cancer cells and that resemble developmental programs. SOX2 is one of the key pluripotency transcription factors, expressed during embryonic development and active in adult stem cells. In cancer, SOX2 is frequently dysregulated and associated with tumor stemness and poor patient survival. SOX2 expression is suppressed in differentiated cells by tumor suppressor proteins that form a transcriptional repressive complex. We previously identified some of these proteins and found that their absence combined with deficiency in Trp53, leads to maximal dysregulated expression of Sox2. Using cancer cell lines of different origin and with different p53 status, we show here that manipulating TP53 to restore or decrease its activity results in repression or induction of SOX2, respectively. Mechanistically, we observed that the regulation of SOX2 expression by TP53 is transcriptional and identified Trp53 bound to the promoter region and the SRR2 enhancer of Sox2. Forcing high levels of SOX2 in cancer cells leads to morphological changes that molecularly correspond to the acquisition of a more mesenchymal phenotype correlating with an increased migratory capacity. Finally, the analysis of human breast cancer samples shows that this correlation between TP53 status, levels of expression of SOX2 and a more metastatic phenotype is also observed in cancer patients. Our results support the notion that lack of TP53 in tumor cells results in deregulated expression of developmental gene SOX2 with phenotypic consequences related with increased malignization. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/623640v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@15e8df8org.highwire.dtl.DTLVardef@baa5e5org.highwire.dtl.DTLVardef@1e181aaorg.highwire.dtl.DTLVardef@7c3f0_HPS_FORMAT_FIGEXP M_FIG C_FIG Novelty and ImpactOur work demonstrates that TP53 regulates transcriptionally SOX2 through binding to its promoter and the SRR2 enhancer. Increased expression of SOX2 promotes an EMT and increased migration. Breast cancer patients with genetic alteration of TP53 show increased levels of SOX2 and a more metastatic phenotype. This work is a key demonstration of an additional effect of genetic alterations of TP53, leading to de-repression of SOX2 and alteration of cancer cell plasticity with important phenotypic consequences.

cancer biology↗

bioRxiv2023

Epigenetic misactivation of a distal developmental enhancer cluster drives SOX2 overexpression in breast and lung cancer

Enhancer reprogramming has been proposed as a key source of transcriptional dysregulation during tumorigenesis, but the molecular mechanisms underlying this process remain unclear. Here, we identify an enhancer cluster required for normal development that is aberrantly activated in breast and lung carcinoma. Deletion of the SRR124-134 cluster disrupts transcription of the SOX2 oncogene and dysregulates genome-wide chromatin accessibility in cancer cells. Analysis of primary tumors reveals a correlation between chromatin accessibility at this cluster and SOX2 overexpression in breast and lung cancer patients. We demonstrate that FOXA1 is an activator and NFIB is a repressor of SRR124-134 activity and SOX2 transcription in cancer cells, revealing a co-opting of the regulatory mechanisms involved in early development. Notably, we show that the conserved SRR124 and SRR134 regions are essential during mouse development, where homozygous deletion results in the lethal failure of esophageal-tracheal separation. These findings provide insights into how developmental enhancers can be reprogrammed during tumorigenesis and underscore the importance of understanding enhancer dynamics during development and disease.

genomics↗

bioRxiv2019

KLF4 protein stability regulated by interaction with pluripotency transcription factors overrides transcriptional control

Embryonic stem (ES) cells are regulated by a network of transcription factors which maintain the pluripotent state. Differentiation relies on downregulation of pluripotency transcription factors disrupting this network. While investigating transcriptional regulation of the pluripotency transcription factor Klf4, we observed homozygous deletion of distal enhancers caused 17 fold decrease in Klf4 transcript but surprisingly decreased protein levels by less than 2 fold indicating post-transcriptional control of KLF4 protein overrides transcriptional control. The lack of sensitivity of KLF4 to transcription is due to high protein stability (half-life >24hr). This stability is context dependent and disrupted during differentiation, evidenced by a shift to a half-life of <2hr. KLF4 protein stability is maintained through interaction with other pluripotency transcription factors (NANOG, SOX2 and STAT3) that together facilitate association of KLF4 with RNA polymerase II. In addition, the KLF4 DNA binding and transactivation domains are required for optimal KLF4 protein stability. Post-translational modification of KLF4 destabilizes the protein as cells exit the pluripotent state and mutations that prevent this destabilization also prevent differentiation. These data indicate the core pluripotency transcription factors are integrated by post-translational mechanisms to maintain the pluripotent state, and identify mutations that increase KLF4 protein stability while maintaining transcription factor function.

developmental biology↗