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

Abstract

Melanoma 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.

Quantitative landscapes reveal trajectories of cell-state transitions associated with drug resistance in melanoma

“…Besides de-differentiation, recent studies have identified alternate pathways to therapy resistance [16][17][18] . Single cell profiling of patient-derived xenograft models revealed an alternate resistance pathway where cells increase expression of pigmentation genes and are referred to as hyper-pigmented 19 .…”

Stabilization of β-catenin promotes melanocyte specification at the expense of the Schwann cell lineage

“…FOXD3 is not the only gene that is repressed by MITF. Indeed, numerous examples of genes ( PTEN , CDH1 , GATA6 ) are repressed by MITF ( Berico et al, 2021 ; Dilshat et al, 2021 ; Hamm et al, 2021 ).…”

Epigenetic Mechanisms Underlying Melanoma Resistance to Immune and Targeted Therapies

“…Additionally, BMI1 epigenetic regulation demonstrates that melanoma cell states are not as binary (invasive or proliferative) as typically described; paradoxical epigenomic states exist which enable MITF alterations without proliferation changes or shifts in therapeutic BRAFi sensitivity. Melanocytic, intermediate, mesenchymal-like, and mitotic states are detectable in drug-naïve tumors [ 203 ], while NCSC, SMC, pigmented, and IFN-active states arise upon drug treatment [ 111 , 167 , 187 ]. The emergence of an IFN-active state in PDX models elicits particular interest due to the absence of functional immune cells.…”

“…Additionally, MITF activity does not simply correlate with expression levels but also correlates with cell background, which dictates MITF protein stability [ 168 ], subcellular localization [ 169 ], protein interactors [ 170 , 171 ], microRNA regulation [ 172 , 173 , 174 , 175 ], DNA binding affinity [ 176 ], and DNA accessibility [ 64 ]. Furthermore, MITF activity depends on tumor microenvironment (TME) conditions, such as nutrient depletion [ 177 , 178 ], immune surveillance and inflammation [ 179 , 180 , 181 ], heterotypic interactions with normal cells [ 182 ], hypoxia [ 183 , 184 ], extracellular matrix (ECM) composition [ 185 ], and drug treatment [ 111 , 180 , 186 , 187 ]. Hence, an integrative adaptive response tuning MITF activity alters a cell’s probability of adopting a particular phenotypic state [ 167 , 188 ].…”