Dual targeting of AMRC12 and Malassezia globosa disrupts MYC liquid condensates-driven nuclear pore complex biogenesis in neuroblastoma

TL;DR

This study shows that targeting ARMC12 and a fungus called Malassezia globosa can disrupt cancer progression in neuroblastoma by interfering with nuclear pore formation.

Contribution

The novel contribution is identifying ARMC12 and Malassezia globosa as dual targets for disrupting MYC-driven nuclear pore complex biogenesis in neuroblastoma.

Findings

ARMC12 interacts with MYC to promote nuclear pore complex biogenesis in neuroblastoma.

MGL_0381 from Malassezia globosa enhances MYC activity and cancer progression.

Inhibitors of ARMC12-MYC and MGL_0381-MYC interactions reduce tumor aggressiveness.

Abstract

Rationale: Neuroblastoma (NB) is a predominant extra-cranial malignancy in childhood, while molecular drivers of its progression and effective treatment strategies have yet to be clarified.

Methods: RNA sequencing was performed to identify transcriptional regulators and corresponding target genes. To explore the biological effects and underlying mechanisms of these regulators, a comprehensive methodology was utilized, encompassing chromatin immunoprecipitation, dual-luciferase reporter assay, qRT-PCR, western blot, alongside gene over-expression and silencing techniques, co-immunoprecipitation, and mass spectrometry. The MTT assay, soft agar colony formation, Matrigel invasion, and nude mouse xenograft models were applied to assess oncogenic properties. Patient survival was analyzed using the log-rank test.

Results: Armadillo repeat containing 12 (ARMC12) was identified as a MYC-interacting modulator within liquid condensates to up-regulate critical nucleoporin-encoding targets (NUP62/NUP93/NUP98), which promoted nuclear pore complex (NPC) biogenesis to facilitate nuclear trafficking of oncogenic effectors, thereby enhancing invasion and metastasis of NB. As a protein within extracellular vesicles of Malassezia globosa colonizing NB tissues, MGL_0381 also facilitated MYC transactivation via physical interaction to accelerate NPC biogenesis and NB progression. Tioconazole (TCZ) and UU-T02 were identified as efficient inhibitors blocking ARMC12-MYC and MGL_0381-MYC interaction, and synergistically reduced NPC number and aggressive features of NB. High ARMC12, MYC, NUP62, NUP93, or NUP98 levels served as markers of unfavorable patient outcomes in clinical cohorts.

Conclusions: These findings collectively demonstrate that dual targeting of AMRC12 and Malassezia globosa disrupts MYC liquid condensates-driven NPC biogenesis during NB progression.

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