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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, how BRN2 functions during the metastatic process of melanoma remains largely unknown. We therefore investigated the effects 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. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE145806 | GEO | 2020/02/25

REPOSITORIES: GEO

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Project description:Radiation and chemotherapy represent standard-of-care cancer treatments, however most treated patients eventually experience tumor recurrence, treatment failure and metastatic dissemination with fatal consequences. To elucidate molecular mechanisms of resistance to radio- and chemo-therapy, we exposed human cancer cell lines (HeLa, MCF-7, and DU145) to clinically relevant doses of 5-azacytidine or ionizing radiation and compared the transcript profiles of all surviving cell subpopulations including non-adherent fraction. Stress-mobilized non-adherent cell fractions differed from other survivors in deregulation of hundreds of genes including those involved in interferon response. Exposure of cancer cells to interferon-gamma but not interferon-beta resulted in development of a heterogeneous non-adherent fraction comprising, besides apoptotic/necrotic cells, also live cells featuring active Notch signaling and expressing stem cell markers. Interferon-gamma-mediated loss of adhesion and anoikis-resistance required active Erk pathway interlinked with interferon signaling by IRF1, as chemical inhibition of MEK or siRNA-mediated knockdown of Erk1/2 and IRF1 prevented mobilization of the surviving non-adherent population. Noteworthy, among the top scoring genes upregulated in surviving non-adherent tumor cells induced by 5-azacytidine or irradiation was a skin-specific protein suprabasin (SBSN), a recently identified oncoprotein. SBSN expression required the activity of the MEK/Erk pathway, and siRNA-mediated knockdown of SBSN resulted in suppression of the non-adherent fraction in irradiated, interferon-gamma- and 5-azacytidine-treated cells, respectively. Consistently, ectopic expression of SBSN isoforms enhanced the non-adherent phenotype, suggesting functional participation of SBSN in genotoxic stress-induced phenotypic plasticity and stress resistance. The stress-induced expression of skin protein(s) in a subset of cancer cells indicates partial induction of a keratinocyte-like expression program. Overall, we propose that IFN and Erk signaling drive the heterogeneous response of cancer cells to genotoxic therapies and expression of keratinocyte-specific genes as key players in mobilization and survival of cancer stem-like cells, with implications for cancer evolution and therapy resistance.

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BRN2 expression increases anoikis resistance in melanoma.

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