Is TFIIH the new Achilles heel of cancer cells?

International audienceTFIIH is a 10-subunit complex involved in transcription and DNA repair. It contains several enzymatic activities including a ATP-dependent DNA translocase in XPB and a cyclin-dependent kinase in CDK7. Recently the discovery of several XPB and CDK7 inhibitors with specific impact on the transcriptional addiction of many tumors pinpointed these activities as potential target in cancer chemotherapy. Unexpectedly a basal transcription factor involved in global mRNA expression now emerges a one of the most clinically promising Achilles heels of cancerous cells. These inhibitors also proved to be useful tools to unveil new functions of TFIIH in gene expression

Epigenetic Mechanisms Underlying Melanoma Resistance to Immune and Targeted Therapies

Melanoma is an aggressive skin cancer reliant on early detection for high likelihood of successful treatment. Solar UV exposure transforms melanocytes into highly mutated tumor cells that metastasize to the liver, lungs, and brain. Even upon resection of the primary tumor, almost thirty percent of patients succumb to melanoma within twenty years. Identification of key melanoma genetic drivers led to the development of pharmacological BRAFV600E and MEK inhibitors, significantly improving metastatic patient outcomes over traditional cytotoxic chemotherapy or pioneering IFN-α and IL-2 immune therapies. Checkpoint blockade inhibitors releasing the immunosuppressive effects of CTLA-4 or PD-1 proved to be even more effective and are the standard first-line treatment. Despite these major improvements, durable responses to immunotherapy and targeted therapy have been hindered by intrinsic or acquired resistance. In addition to gained or selected genetic alterations, cellular plasticity conferred by epigenetic reprogramming is emerging as a driver of therapy resistance. Epigenetic regulation of chromatin accessibility drives gene expression and establishes distinct transcriptional cell states. Here we review how aberrant chromatin, transcriptional, and epigenetic regulation contribute to therapy resistance and discuss how targeting these programs sensitizes melanoma cells to immune and targeted therapies

Active mRNA degradation by EXD2 nuclease elicits recovery of transcription after genotoxic stress

Here the authors show that the exonuclease EXD2 is involved in the recovery of class II gene transcription after UV irradiation. EXD2 travels from the mitochondria to the nucleus to interact with RNA Pol II and degrade new synthetized mRNA to allow transcription following DNA repair

CDK7 and MITF repress a transcription program involved in survival and drug tolerance in melanoma

International audienceMelanoma cell phenotype switching between differentiated melanocytic and undifferentiated mesenchymal-like states drives metastasis and drug resistance. CDK7 is the serine/threonine kinase of the basal transcription factor TFIIH. We show that dedifferentiation of melanocytic-type melanoma cells into mesenchymal-like cells and acquisition of tolerance to targeted therapies is achieved through chronic inhibition of CDK7. In addition to emergence of a mesenchymal-type signature, we identify a GATA6-dependent gene expression program comprising genes such as AMIGO2 or ABCG2 involved in melanoma survival or targeted drug tolerance, respectively. Mechanistically, we show that CDK7 drives expression of the melanocyte lineage transcription factor MITF that in turn binds to an intronic region of GATA6 to repress its expression in melanocytic-type cells. We show that GATA6 expression is activated in MITF-low melanoma cells of patient-derived xenografts. Taken together, our data show how the poorly characterized repressive function of MITF in melanoma participates in a molecular cascade regulating activation of a transcriptional program involved in survival and drug resistance in melanoma