BRN2 expression increases anoikis resistance in melanoma

Abstract

Melanoma tumors are highly heterogeneous, comprising of many cell populations that vary in their potential for growth and invasion. Differential transcription factor expression contributes to these phenotypic traits. BRN2, a member of the POU domain family of transcription factors is thought to play important roles in melanoma invasion and metastasis. However, the function of BRN2 during the metastatic process of melanoma remains largely unknown. We therefore investigated the effect of BRN2 expression in melanoma cells with no or low constitutive expression using a doxycycline-inducible system. Induction of BRN2 expression led to reduced proliferation and partial resistance to an inhibitor of mutated BRAF. Whole-genome profiling analysis revealed novel targets and signaling pathway changes related to prevention of cell death induced by detachment from the extracellular matrix, known as anoikis resistance. Further investigation confirmed increased survival of BRN2-expressing cell lines in non-adherent conditions. Functionally, expression of BRN2 promoted induction of c-MET levels as well as increased phosphorylation of STAT3. Treatment with crizotinib, a c-MET inhibitor, decreased cellular viability of BRN2-expressing cells under non-adherent conditions to death by anoikis. Alternative inhibitors of c-MET showed similar results. These results highlight the importance of a largely overlooked transcription factor in the progression and metastasis of melanoma, and may suggest a strategy to target BRN2-expressing cells resistant to therapy and cell death by anoikis.

FOXD1 promotes dedifferentiation and targeted therapy resistance in melanoma by regulating the expression of connective tissue growth factor

“…Pierce et al found that overexpression of BRN2 can constrain melanoma proliferation and trigger partial resistance of melanoma cells to BRAFi. 47 TWIST1, a basic helix-loop-helix TF, controls melanoma cell invasion, and has recently been found to confer chemoresistance to various cancer cell types. [48][49][50] Another NC-associated gene, ZEB1, was identified as a master regulator of melanoma stemness and resistance toward BRAFi and MEKi.…”

Roles of Aminoacyl-tRNA Synthetases in Cancer

“…Further studies found that TyrRS could facilitate gastric cancer progression and homologous recombination process by regulating phosphatidylinositol 3-kinase (PI3K)/AKT signaling ( Zhang et al, 2020 ). Melanoma is a type of aggressive skin cancer with high heterogeneity ( Pierce and Simmons, 2020 ). WARS could regulate the proliferation, migration and invasion of uveal melanoma cells via inducing the activation of PI3K/AKT/mTOR pathway, suggesting that WARS might be is a novel tumorigenic factor ( Yang et al, 2020 ).…”

Transcriptional regulators and alterations that drive melanoma initiation and progression

“…BRN2 has also been shown to repress MITF expression and mark a distinct subpopulation of MITF-negative melanoma cells. Furthermore, related to its role in promoting melanoma metastasis, BRN2 confers anoikis resistance and promotes metastatic growth after the dissemination of melanoma [ 26 , 27 ]. A separate study identified a previously undocumented role for BRN2 [ 28 ].…”