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Transcriptional repression of IFN?1 by ATF2 confers melanoma resistance to therapy.

ABSTRACT: The resistance of melanoma to current treatment modalities represents a major obstacle for durable therapeutic response, and thus the elucidation of mechanisms of resistance is urgently needed. The crucial functions of activating transcription factor-2 (ATF2) in the development and therapeutic resistance of melanoma have been previously reported, although the precise underlying mechanisms remain unclear. Here, we report a protein kinase C-? (PKC?)- and ATF2-mediated mechanism that facilitates resistance by transcriptionally repressing the expression of interferon-?1 (IFN?1) and downstream type-I IFN signaling that is otherwise induced upon exposure to chemotherapy. Treatment of early-stage melanomas expressing low levels of PKC? with chemotherapies relieves ATF2-mediated transcriptional repression of IFN?1, resulting in impaired S-phase progression, a senescence-like phenotype and increased cell death. This response is lost in late-stage metastatic melanomas expressing high levels of PKC?. Notably, nuclear ATF2 and low expression of IFN?1 in melanoma tumor samples correlates with poor patient responsiveness to biochemotherapy or neoadjuvant IFN-?2a. Conversely, cytosolic ATF2 and induction of IFN?1 coincides with therapeutic responsiveness. Collectively, we identify an IFN?1-dependent, cell-autonomous mechanism that contributes to the therapeutic resistance of melanoma via the PKC?-ATF2 regulatory axis.

SUBMITTER: Lau E

PROVIDER: S-EPMC4558399 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Transcriptional repression of IFNβ1 by ATF2 confers melanoma resistance to therapy.

Lau E E Sedy J J Sander C C Shaw M A MA Feng Y Y Scortegagna M M Claps G G Robinson S S Cheng P P Srivas R R Soonthornvacharin S S Ideker T T Bosenberg M M Gonzalez R R Robinson W W Chanda S K SK Ware C C Dummer R R Hoon D D Kirkwood J M JM Ronai Z A ZA

Oncogene 20150302 46

The resistance of melanoma to current treatment modalities represents a major obstacle for durable therapeutic response, and thus the elucidation of mechanisms of resistance is urgently needed. The crucial functions of activating transcription factor-2 (ATF2) in the development and therapeutic resistance of melanoma have been previously reported, although the precise underlying mechanisms remain unclear. Here, we report a protein kinase C-ɛ (PKCɛ)- and ATF2-mediated mechanism that facilitates re ...[more]

PMID: 25728676

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Project description:BackgroundBRAF inhibitors are widely employed in the treatment of melanoma with the BRAF V600E mutation. However, the development of resistance compromises their therapeutic efficacy. Diverse genomic and transcriptomic alterations are found in BRAF inhibitor resistant melanoma, posing a pressing need for convergent, druggable target that reverse therapy resistant tumor with different resistance mechanisms.MethodsCRISPR-Cas9 screens were performed to identify novel target gene whose inhibition selectively targets A375VR, a BRAF V600E mutant cell line with acquired resistance to vemurafenib. Various in vitro and in vivo assays, including cell competition assay, water soluble tetrazolium (WST) assay, live-dead assay and xenograft assay were performed to confirm synergistic cell death. Liquid Chromatography-Mass Spectrometry analyses quantified polyamine biosynthesis and changes in proteome in vemurafenib resistant melanoma. EIF5A hypusination dependent protein translation and subsequent changes in mitochondrial biogenesis and activity were assayed by O-propargyl-puromycin labeling assay, mitotracker, mitoSOX labeling and seahorse assay. Bioinformatics analyses were used to identify the association of polyamine biosynthesis with BRAF inhibitor resistance and poor prognosis in melanoma patient cohorts.ResultsWe elucidate the role of polyamine biosynthesis and its regulatory mechanisms in promoting BRAF inhibitor resistance. Leveraging CRISPR-Cas9 screens, we identify AMD1 (S-adenosylmethionine decarboxylase 1), a critical enzyme for polyamine biosynthesis, as a druggable target whose inhibition reduces vemurafenib resistance. Metabolomic and proteomic analyses reveal that polyamine biosynthesis is upregulated in vemurafenib-resistant cancer, resulting in enhanced EIF5A hypusination, translation of mitochondrial proteins and oxidative phosphorylation. We also identify that sustained c-Myc levels in vemurafenib-resistant cancer are responsible for elevated polyamine biosynthesis. Inhibition of polyamine biosynthesis or c-Myc reversed vemurafenib resistance both in vitro cell line models and in vivo in a xenograft model. Polyamine biosynthesis signature is associated with poor prognosis and shorter progression free survival after BRAF/MAPK inhibitor treatment in melanoma cohorts, highlighting the clinical relevance of our findings.ConclusionsOur findings delineate the molecular mechanisms involving polyamine-EIF5A hypusination-mitochondrial respiration pathway conferring BRAF inhibitor resistance in melanoma. These targets will serve as effective therapeutic targets that can maximize the therapeutic efficacy of existing BRAF inhibitors.

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Transcriptional repression of IFN?1 by ATF2 confers melanoma resistance to therapy.

Publications

Transcriptional repression of IFNβ1 by ATF2 confers melanoma resistance to therapy.

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