Nuclear Transport Factor 2 (NTF2) suppresses WM983B metastatic melanoma by modifying cell migration, metastasis, and gene expression

Abstract

While changes in nuclear structure and organization are frequently observed in cancer cells, relatively little is known about how nuclear architecture impacts cancer progression and pathology. To begin to address this question, we studied Nuclear Transport Factor 2 (NTF2) because its levels decrease during melanoma progression. We show that increasing NTF2 expression in WM983B metastatic melanoma cells reduces cell proliferation and motility while increasing apoptosis. We also demonstrate that increasing NTF2 expression in these cells significantly inhibits metastasis and prolongs survival of mice. NTF2 levels affect the expression and nuclear positioning of a number of genes associated with cell proliferation and migration, and increasing NTF2 expression leads to changes in nuclear size, nuclear lamin A levels, and chromatin organization. Thus, ectopic expression of NTF2 in WM983B metastatic melanoma abrogates phenotypes associated with advanced stage cancer both in vitro and in vivo, concomitantly altering nuclear and chromatin structure and generating a gene expression profile with characteristics of primary melanoma. We propose that NTF2 is a melanoma tumor suppressor and could be a novel therapeutic target to improve health outcomes of melanoma patients.

Native top-down proteomics reveals EGFR–ERα signaling crosstalk in breast cancer cells dissociates NUTF2 dimers to modulate ERα signaling and cell growth

“…Exogenous NUTF2 suppressed cell proliferation (Figure 5F), as seen in melanoma 40 . The K4Q mutation rescued this phenotype (Figure 5F), suggesting that K4 acetylation blocks the growth-inhibitory activity of NUTF2.…”

Epidemiology, management, and treatment outcomes of metastatic spinal melanoma

“… 58 Additional work in mice has shown that increasing the expression of nuclear transport factor 2 in metastatic melanoma cells reduces cell motility and metastasis. 59 Kratzsch et al demonstrate that targeting tumor growth and tumor cell interactions with vasculature using inhibitors of mammalian target of rapamycin and vascular endothelial growth factor receptors may delay development of symptomatic spinal metastasis, though therapeutic efficacy was only mild. 60 Collectively, these studies suggest that elucidating the molecular underpinnings of the metastatic cascade could reveal novel approaches for prophylactic treatment of metastatic spinal melanoma.…”

Nuclear growth and import can be uncoupled

“…With respect to disease, nuclear morphometrics and chromatin condensation state are used as cancer biomarkers ( Damodaran et al. , 2019 ; Vukovic et al. , 2021 ).…”