Targeting SKA3 suppresses the proliferation and chemoresistance of laryngeal squamous cell carcinoma via impairing PLK1\u2013AKT axis-mediated glycolysis

Wei Gao,Jiajia Cui,Shuxin Wen,Yuliang Zhang,Tao Yang,Wanglai Hu,Fengsheng Dai,Changming An,Wei Xu,Xian Zheng ,Huina Guo,Hongjie Luo,Li Li,Xuting Xue,Yunfeng Bo,Lei Jin,Teng Ma,Huizheng Li,Yu Zhang,Yujia Guo,Dongli Yang,Linshi Zhang,Yan Lü ,Min Niu,Rui Hou,Yongyan Wu

doi:10.1038/s41419-020-03104-6

Abstract

Spindle and kinetochore-associated complex subunit 3 (SKA3) is a well-known regulator of chromosome separation and cell division, which plays an important role in cell proliferation. However, the mechanism of SKA3 regulating tumor proliferation via reprogramming metabolism is unknown. Here, SKA3 is identified as an oncogene in laryngeal squamous cell carcinoma (LSCC), and high levels of SKA3 are closely associated with malignant progression and poor prognosis. In vitro and in vivo experiments demonstrate that SKA3 promotes LSCC cell proliferation and chemoresistance through a novel role of reprogramming glycolytic metabolism. Further studies reveal the downstream mechanisms of SKA3, which can bind and stabilize polo-like kinase 1 (PLK1) protein via suppressing ubiquitin-mediated degradation. The accumulation of PLK1 activates AKT and thus upregulates glycolytic enzymes HK2, PFKFB3, and PDK1, resulting in enhancement of glycolysis. Furthermore, our data reveal that phosphorylation at Thr360 of SKA3 is critical for its binding to PLK1 and the increase in glycolysis. Collectively, the novel oncogenic signal axis “SKA3-PLK1-AKT” plays a critical role in the glycolysis of LSCC. SKA3 may serve as a prognostic biomarker and therapeutic target, providing a potential strategy for proliferation inhibition and chemosensitization in tumors, especially for LSCC patients with PLK1 inhibitor resistance.

Highlights

Laryngeal squamous cell carcinoma (LSCC) is the second most frequent tumor of the respiratory tract or head and neck carcinoma[1,2]
As an important component of the spindle and kinetochore-related complexes[29], SKA3 is essential for regulating mitosis with NDC80 complex and controlling cell proliferation and apoptosis[26,30]
EGFR mutation is rare in laryngeal squamous cell carcinoma (LSCC), SKA3-mediated AKT activation mainly depends on the serine/threonineprotein kinase polo-like kinase 1 (PLK1) as silencing of PLK1 significantly attenuated the increase in phosphorylation of AKT (p-AKT) caused by SKA3 overexpression (Fig. 4F), indicating the context-dependent regulation of AKT

Summary

Introduction

Laryngeal squamous cell carcinoma (LSCC) is the second most frequent tumor of the respiratory tract or head and neck carcinoma[1,2]. The onset of LSCC is occult, accounting for 60% incidence of patients with advanced stages (clinical stages 3 and 4) upon diagnosis[1,6]. Those with the highest risk of recurrence are usually diagnosed in the first 2–3 years after surgery[7]. Secondary primary tumors are often diagnosed in patients whose initial lesion is controlled[8]. These major adverse factors significantly decrease the efficacy of long-term treatment and the survival rates of patients[9]. It is necessary to identify the molecular regulatory mechanisms underlying the progression of LSCC and the development of chemoresistance, by which to identify novel therapeutic targets, and developing new therapeutic strategies for LSCC patients

Methods

Results

Conclusion