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Skp2-mediated ubiquitination and mitochondrial localization of Akt drive tumor growth and chemoresistance to cisplatin.

Abstract：

:The E3 ligase S-phase kinase-associated protein 2(Skp2) is overexpressed in human cancers and correlated with poor prognosis, but its contributions to tumorigenesis and chemoresistance in nasopharyngeal carcinoma (NPC) are not evident. Herein we show that Skp2 is highly expressed in NPC tumor tissues and cell lines. Knockdown of Skp2 suppresses tumor cell growth, colony formation, glycolysis, and in vivo tumor growth. Skp2 promotes Akt K63-mediated ubiquitination and activation, which is required for EGF-induced Akt mitochondrial localization. Importantly, K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization. Overexpression of Skp2 impaired the intrinsic apoptotic pathway and confers cisplatin resistance. Moreover, ectopic expression of Myr-Akt1 or phosphomimetic HK2-T473D rescued cisplatin-induced tumor suppression in Skp2 knockdown stable cells. Also, depletion of Akt ubiquitination enhances the antitumor efficacy of cisplatin in vitro and in vivo. Finally, we demonstrated that Skp2 is positively correlated with p-Akt and HK2 in NPC tumor tissues. This study highlights the clinical value of Skp2 targeting in NPC treatment.

journal_name

Oncogene

journal_title

Oncogene

authors

Yu X,Wang R,Zhang Y,Zhou L,Wang W,Liu H,Li W

doi

10.1038/s41388-019-0955-7

subject

Has Abstract

pub_date

2019-12-01 00:00:00

pages

7457-7472

issue

50

eissn

0950-9232

issn

1476-5594

pii

10.1038/s41388-019-0955-7

journal_volume

38

pub_type

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