Tumor-promoting properties of karyopherin β1 in melanoma by stabilizing Ras-GTPase-activating protein SH3 domain-binding protein 1

Abstract

The nuclear import receptor karyopherin β1 (KPNB1), a member of the Karyopherin protein family, is reported to be overexpressed in various cancers and promote carcinogenesis. By analyzing the correlation between the expression of KPNB1 and the overall survival rate of melanoma patients, we found that melanoma patients with higher expression of KPNB1 had worse survival. Furthermore, the database analyzed that the KPNB1 mRNA level was higher in melanoma samples than that in skin nevus tissues. We thus proposed that KPNB1 played a role in promoting melanoma development, and conducted gain-of- and loss-of-function experiments to test our hypothesis. We found that KPNB1 knockdown significantly retarded the growth and metastasis of melanoma cells in vitro and in vivo, and increased their sensitivity towards the anti-tumor drug cisplatin. KPNB1 overexpression had opposite effects. Notably, in melanoma cells, KPNB1 overexpression significantly decreased Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) protein level, which was also overexpressed in melanoma samples and enhanced malignant behaviors of melanoma cells. We further demonstrated that KPNB1 overexpression induced deubiquitination of G3BP1, and prevented its degradation. However, KPNB1 overexpression hardly affected the nuclear translocation of G3BP1. Additionally, alterations induced by KPNB1 overexpression were partly reversed by G3BP1 inhibition. Therefore, the results suggest that KPNB1 may promote melanoma progression by stabilizing the G3BP1 protein. KPNB1-G3BP1 axis represents a potential therapeutic targetable node for melanoma.

Therapeutic targeting of nuclear export and import receptors in cancer and their potential in combination chemotherapy

“…KPNB1 overexpression is closely linked with disease progression and worsened prognostic outcomes in melanoma patients 195 . Cellular melanoma models display reduced tumorgenicity and metastatic potential following KPNB1 knockdown, whereas synthetic overexpression amplifies the carcinogenic function of KPNB1 and enhances the aggressive melanoma phenotype 195 . Ras‐GTPase‐activating protein SH3‐binding protein 1 (G3BP1) is a multifunctional RNA‐binding protein that is involved in stress granule formation 196 .…”

“…Interestingly, KPNB1 was shown to interact with G3BP1 and stabilize its protein levels via reduced ubiquitination; however, genetic knockdown of KPNB1 had opposing effects. Furthermore, genetic inhibition of G3BP1 demonstrates anti‐melanoma effects in vitro and negates the survival advantage incurred by KPNB1 overexpression 195 . It is possible that the nuclear exclusion of cargoes following KPNB1 genetic inhibition initiates the ubiquitination and subsequent degradation of various cytoplasmic proteins, including G3BP1, to retain a proteostatic balance; in melanoma this gives rise to anti‐cancer activity as well as enhanced cell line and murine xenograft sensitivity to cisplatin 94,195 .…”

“…Slowed tumour growth in mouse xenograft models of melanoma, prostate cancer, and ovarian cancer 87 , 92 , 93 , 94 , 95 , 195 …”

“… 195 Cellular melanoma models display reduced tumorgenicity and metastatic potential following KPNB1 knockdown, whereas synthetic overexpression amplifies the carcinogenic function of KPNB1 and enhances the aggressive melanoma phenotype. 195 Ras‐GTPase‐activating protein SH3‐binding protein 1 (G3BP1) is a multifunctional RNA‐binding protein that is involved in stress granule formation. 196 G3BP1 is upregulated in various cancers, including melanoma, and is known to contribute towards disease progression and chemoresistance.…”

“…Furthermore, genetic inhibition of G3BP1 demonstrates anti‐melanoma effects in vitro and negates the survival advantage incurred by KPNB1 overexpression. 195 It is possible that the nuclear exclusion of cargoes following KPNB1 genetic inhibition initiates the ubiquitination and subsequent degradation of various cytoplasmic proteins, including G3BP1, to retain a proteostatic balance; in melanoma this gives rise to anti‐cancer activity as well as enhanced cell line and murine xenograft sensitivity to cisplatin. 94 , 195 However, further investigation into the oncogenic functions of both G3BP1 and KPNB1 in melanoma is warranted.…”