Biology subjects

Sole, L.

Publications and source records attributed to Sole, L..

3 recordsLinked to original sources

bioRxiv2023

Separation-of-function mutants reveal the NF-κB-independent involvement of IκBα in the regulation of stem cell and oncogenic programs

We previously demonstrated that the NF-{kappa}B inhibitor I{kappa}B binds the chromatin together with PRC2 to regulate a subset of developmental- and stem cell-related genes. This alternative function has been elusive in both physiological and disease conditions because of the predominant role of I{kappa}B as a negative regulator of NF-{kappa}B. We here uniquely characterize specific residues of I{kappa}B that allow the generation of separation-of-function (SOF) mutants that are defective for either NF-{kappa}B-related (SOF{Delta}NF-{kappa}B) or chromatin-related (SOF{Delta}H2A,H4) activities. Expression of I{kappa}B SOF{Delta}NF-{kappa}B, but not SOF{Delta}H2A/H4, is sufficient to negatively regulate a specific stemness program in intestinal cells, thus rescuing the differentiation blockage imposed by I{kappa}B deficiency. In contrast, full I{kappa}B activity is required for regulating clonogenic/tumor-initiating activity of colorectal cancer cells. Our data indicate that SOF mutants represent an exclusive tool for studying I{kappa}B functions in physiology and disease, and identified I{kappa}B as a robust prognosis biomarker for human cancer.

cell biology↗

bioRxiv2023

IKK1 kinase coordinates BRD4 and JAK/STAT signaling to subvert DNA damage-based anticancer therapy

Activation of the IKK kinase complex has recurrently been linked to colorectal cancer (CRC) initiation and progression. However, identification of downstream effectors other than NF-{kappa}B has remained elusive. Analysis of IKK-dependent substrates after UV-treatment revealed that BRD4 phosphorylation by IKK is required for chromatin-binding dynamics upon damage. Moreover, IKK induces the NF-{kappa}B-dependent transcription of LIF leading to STAT3 activation, association of BRD4 to STAT3 and recruitment to specific target genes. IKK abrogation results in defective BRD4 and STAT3 function leading to irreparable DNA damage and apoptotic cell death upon different stimuli. Simultaneous inhibition of BRAF-dependent IKK activity or BRD4 and the JAK/STAT pathway enhanced the therapeutic potential of 5-FU plus irinotecan in CRC cells, and is curative in a chemotherapy-resistant CRC xenograft model. Coordinated expression of LIF and IKK is a poor prognosis marker for CRC patients. Our data uncover a functional link between IKK, BRD4 and JAK/STAT signaling with clinical relevance.

cancer biology↗

bioRxiv2021

Chemotherapy induces a YAP1-dependent fetal conversion to human Colorectal Cancer cells that is predictive of poor patient outcome

Current therapy against colorectal cancer is based on DNA-damaging agents that eradicate highly proliferative malignant cells. Whether sublethal chemotherapy affects tumor cell behavior and impacts on patient outcome is primarily unstudied. We now show that sublethal chemotherapy imposes a quiescent-like state to p53 wildtype human colorectal cancer (CRC) cells that is linked to the acquisition of a fetal phenotype downstream of YAP1, similar to that observed after intestinal damage. CRC cells displaying this fetal phenotype exhibit tumor- initiating activity comparable to untreated cells but superior metastatic capacity. Notably, nuclear YAP1 accumulation, or detection of the fetal signature in tumors predict poor prognosis in CRC patients carrying p53 wildtype tumors. Collectively, our results uncover a potential adverse response of tumor cells to suboptimal chemotherapy, and identify nuclear YAP1 and fetal conversion of colorectal tumors as biomarkers for prognosis and therapy prescription. Statement of significanceChemotherapy induces a quiescent-like phenotype to colorectal cancer cells that is linked to the acquisition of a YAP1-dependent fetal signature. Notably, this signature is predictive of patient outcome in different cohorts of human colorectal cancer.

cancer biology↗