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Inhibition of Karyopherin β1-mediated nuclear import of lineage-defining TFs in small cell lung cancer

ABSTRACT: Inhibition of Karyopherin β1-mediated nuclear import of lineage-defining TFs in small cell lung cancer

PROVIDER: PRJNA767882 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16155700.fastq.gz	Fastqsanger.gz
	SRR16155701.fastq.gz	Fastqsanger.gz
	SRR16155702.fastq.gz	Fastqsanger.gz
	SRR16155703.fastq.gz	Fastqsanger.gz
	SRR16155704.fastq.gz	Fastqsanger.gz

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Inhibition of Karyopherin β1-mediated nuclear import of lineage-defining TFs in small cell lung cancer

Project description:Extensive genomic studies support the classification of small cell lung cancer (SCLC) into subtypes based on expression of lineage-defining transcription factors including ASCL1 and NEUROD1, which together account for ~80% of this disease. ASCL1 and NEUROD1 activate SCLC oncogene expression and drive distinct transcriptional programs. ASCL1 is also required for tumorigenesis in SCLC mouse models, and both ASCL1 and NEUROD1 maintain the in vitro growth and oncogenic properties of ASCL1+ or NEUROD1+ SCLC cell lines. Strategies to inhibit ASCL1 and NEUROD1 may therefore represent an attractive, targeted SCLC therapy and provide a tool to investigate the underlying plasticity of the predominant SCLC subtypes. However, ASCL1 and NEUROD1 have long been considered “undruggable” vulnerabilities. Here, we use a proteomic approach to identify Karyopherin β1 (KPNB1) as a nuclear import receptor for ASCL1 and NEUROD1 in SCLC, and demonstrate that the inhibition of KPNB1 using a variety of genetic or pharmacological approaches leads to impaired ASCL1 and NEUROD1 nuclear accumulation and transcriptional activity. Pharmacological targeting of KPNB1 preferentially disrupts ASCL1/NEUROD1+ SCLC cell line growth in vitro and ASCL1+ tumor growth in an in vivo patient derived xenograft (PDX) model of SCLC.

2022-09-20 | GSE185187 | GEO

Inhibition of Karyopherin β1-Mediated Nuclear Import Disrupts Oncogenic Lineage-Defining Transcription Factor Activity in Small Cell Lung Cancer.

Project description:Genomic studies support the classification of small cell lung cancer (SCLC) into subtypes based on the expression of lineage-defining transcription factors ASCL1 and NEUROD1, which together are expressed in ∼86% of SCLC. ASCL1 and NEUROD1 activate SCLC oncogene expression, drive distinct transcriptional programs, and maintain the in vitro growth and oncogenic properties of ASCL1 or NEUROD1-expressing SCLC. ASCL1 is also required for tumor formation in SCLC mouse models. A strategy to inhibit the activity of these oncogenic drivers may therefore provide both a targeted therapy for the predominant SCLC subtypes and a tool to investigate the underlying lineage plasticity of established SCLC tumors. However, there are no known agents that inhibit ASCL1 or NEUROD1 function. In this study, we identify a novel strategy to pharmacologically target ASCL1 and NEUROD1 activity in SCLC by exploiting the nuclear localization required for the function of these transcription factors. Karyopherin β1 (KPNB1) was identified as a nuclear import receptor for both ASCL1 and NEUROD1 in SCLC, and inhibition of KPNB1 led to impaired ASCL1 and NEUROD1 nuclear accumulation and transcriptional activity. Pharmacologic targeting of KPNB1 preferentially disrupted the growth of ASCL1+ and NEUROD1+ SCLC cells in vitro and suppressed ASCL1+ tumor growth in vivo, an effect mediated by a combination of impaired ASCL1 downstream target expression, cell-cycle activity, and proteostasis. These findings broaden the support for targeting nuclear transport as an anticancer therapeutic strategy and have implications for targeting lineage-transcription factors in tumors beyond SCLC. The identification of KPNB1 as a nuclear import receptor for lineage-defining transcription factors in SCLC reveals a viable therapeutic strategy for cancer treatment.

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Ibetazol, a novel inhibitor of importin β1-mediated nuclear import.

Project description:Nucleocytoplasmatic transport plays an essential role in eukaryotic cell homeostasis and is mediated by karyopherins. Importin β1 (KPNB1) and its adaptor protein importin α1 (KPNA2) are the best-characterized karyopherins that effect nuclear import. Here, we identify a novel small-molecule inhibitor of the importin β1-mediated nuclear import. We design a reporter cell line by stably tagging endogenous importin α1 with a fluorescent protein to screen for compounds affecting its subcellular localization. We identify a series of compounds that trigger cytoplasmatic accumulation of importin α1. The lead compound, ibetazol, is further characterized in a broad sequence of cellular nuclear transport assays. Ibetazol is shown to inhibit all importin β1-mediated nuclear import quickly and specifically, without affecting transport mediated by other karyopherins. Detailed molecular mechanism of action studies demonstrate that ibetazol inhibits importin β1 by covalently targeting Cys585. In summary, ibetazol is a novel small molecule inhibitor of importin β1 enabling pharmacological inhibition of the importin β1-mediated nuclear import process with wide applicability in different fields.

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AKIRIN2 controls the nuclear import of proteasomes in vertebrates

Project description:Protein expression and turnover are controlled through a complex interplay of transcriptional, post-transcriptional and post-translational mechanisms to enable spatial and temporal regulation of cellular processes. To systematically elucidate such gene regulatory networks, we developed a CRISPR screening assay based on time-controlled Cas9 mutagenesis, intracellular immunostaining and fluorescence-activated cell sorting that enables the identification of regulatory factors independent of their effects on cellular fitness. We pioneered this approach by systematically probing the regulation of the transcription factor MYC, a master regulator of cell growth. Our screens uncover a highly conserved protein, AKIRIN2, that is essentially required for nuclear protein degradation. We found that AKIRIN2 forms homodimers that directly bind to fully assembled 20S proteasomes to mediate their nuclear import. During mitosis, proteasomes are excluded from condensing chromatin and re-imported into newly formed daughter nuclei in a highly dynamic, AKIRIN2-dependent process. Cells undergoing mitosis in the absence of AKIRIN2 become devoid of nuclear proteasomes, rapidly causing accumulation of MYC and other nuclear proteins. Collectively, our study reveals a dedicated pathway controlling the nuclear import of proteasomes in vertebrates and establishes a scalable approach to decipher regulators in essential cellular processes.

2021-08-27 | GSE157663 | GEO

AKIRIN2 controls the nuclear import of proteasomes in vertebrates

Project description:AKIRIN2 controls the nuclear import of proteasomes in vertebrates

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Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy

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