Targeting XPO6 inhibits prostate cancer progression and enhances the suppressive efficacy of docetaxel

Abstract

Background Although XPO6, one of the Exportin family members, functions in malignant progression of certain types of cancer, its role in prostate cancer (PCa) has not been elucidated. Herein, we investigated the oncogenic effect and clarified the downstream mechanism of XPO6 in PCa cells. Methods We detected the expression level of XPO6 in PCa tissues by immunohistochemistry (IHC) and analyzed the correlation between clinicopathological characteristics and XPO6 level based on TCGA database. The effects of XPO6 in the proliferation and migration or resistance to docetaxel (DTX) in PCa cells were assessed using CCK8, colony formation, wound-healing and Transwell assays. Mice experiments were performed to investigate the role of XPO6 in tumor progression and DTX effect in vivo. Further, functional analysis of DEGs revealed the correlation of XPO6 with Hippo pathway and XPO6 could promote the expression and nuclear translocation of YAP1 protein. Furthermore, blocking Hippo pathway with YAP1 inhibitor leads to the loss of XPO6-mediated regulation of biological functions. Results XPO6 was highly expressed and positively correlated with the clinicopathological characteristics of PCa. Functional experiments indicated that XPO6 could promote tumor development and DTX resistance in PCa. Mechanistically, we further confirmed that XPO6 could regulate Hippo pathway via mediating YAP1 protein expression and nuclear translocation thereby promoting PCa progression and chemotherapeutic resistance. Conclusion In conclusion, our research reveals that XPO6 potentially function as an oncogene and promotes DTX resistance of PCa, suggesting that XPO6 could be both a potential prognostic marker as well as a therapeutic target to effectively overcome DTX resistance.

Comprehensive Analysis of Exportins Expression and its Prognostic Significance in Colon Adenocarcinoma: Insights from Public Databases

“…XPO4 is upregulated in prostate cancer and downregulated in hepatocellular carcinoma [28,29]. XPO6 has been exclusively identified as an oncogene in prostate and breast cancer [30,31]. XPO7 was also found to be dysregulated in ovarian cancer, prostate cancer, liver cancer, and breast cancer [27,[32][33][34].…”

Impact of Pan-Cancer Analysis of The Exportins Family on Prognosis, The Tumour Microenvironment and Its Potential Therapeutic Efficacy

“…The narrative takes a curious twist with XPO5 in HCC (Li et al 2016), where its diminished expression dovetails with tumor-suppressive attributes, a tale recounted through the lens of inhibited cellular proliferation and other oncological signposts. Meanwhile, XPO6, riding the tide of upregulation in prostate cancer, emerges as a potential protagonist in tumor growth and drug resistance, possibly through its sway over the Hippo-YAP1 signaling pathway (Wang et al 2023). The saga reaches a crescendo with XPO7, whose heightened expression spells doom for prostate cancer outcomes, intensifying malignancy traits in both test tubes and living models.…”