PMID- 33106477
OWN - NLM
STAT- MEDLINE
DCOM- 20210517
LR  - 20231213
IS  - 2041-4889 (Electronic)
VI  - 11
IP  - 10
DP  - 2020 Oct 26
TI  - Targeting SKA3 suppresses the proliferation and chemoresistance of laryngeal 
      squamous cell carcinoma via impairing PLK1-AKT axis-mediated glycolysis.
PG  - 919
LID - 10.1038/s41419-020-03104-6 [doi]
LID - 919
AB  - 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.
FAU - Gao, Wei
AU  - Gao W
AUID- ORCID: 0000-0001-7836-2851
AD  - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital 
      of Shanxi Medical University, 030001, Taiyuan, Shanxi, P.R. China.
AD  - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head 
      and Neck Cancer, First Hospital of Shanxi Medical University, 030001, Taiyuan, 
      Shanxi, P.R. China.
AD  - Department of Otolaryngology Head & Neck Surgery, First Hospital of Shanxi 
      Medical University, 030001, Taiyuan, Shanxi, P.R. China.
AD  - Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical 
      University, 030001, Taiyuan, Shanxi, P.R. China.
AD  - Department of Cell Biology and Genetics, Shanxi Medical University, 030001, 
      Taiyuan, Shanxi, P.R. China.
FAU - Zhang, Yuliang
AU  - Zhang Y
AD  - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital 
      of Shanxi Medical University, 030001, Taiyuan, Shanxi, P.R. China.
AD  - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head 
      and Neck Cancer, First Hospital of Shanxi Medical University, 030001, Taiyuan, 
      Shanxi, P.R. China.
FAU - Luo, Hongjie
AU  - Luo H
AD  - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital 
      of Shanxi Medical University, 030001, Taiyuan, Shanxi, P.R. China.
FAU - Niu, Min
AU  - Niu M
AD  - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital 
      of Shanxi Medical University, 030001, Taiyuan, Shanxi, P.R. China.
AD  - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head 
      and Neck Cancer, First Hospital of Shanxi Medical University, 030001, Taiyuan, 
      Shanxi, P.R. China.
FAU - Zheng, Xiwang
AU  - Zheng X
AD  - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital 
      of Shanxi Medical University, 030001, Taiyuan, Shanxi, P.R. China.
AD  - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head 
      and Neck Cancer, First Hospital of Shanxi Medical University, 030001, Taiyuan, 
      Shanxi, P.R. China.
FAU - Hu, Wanglai
AU  - Hu W
AD  - School of Basic Medical Science, Anhui Medical University, 230032, Hefei, Anhui, 
      P.R. China.
FAU - Cui, Jiajia
AU  - Cui J
AD  - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital 
      of Shanxi Medical University, 030001, Taiyuan, Shanxi, P.R. China.
AD  - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head 
      and Neck Cancer, First Hospital of Shanxi Medical University, 030001, Taiyuan, 
      Shanxi, P.R. China.
FAU - Xue, Xuting
AU  - Xue X
AD  - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital 
      of Shanxi Medical University, 030001, Taiyuan, Shanxi, P.R. China.
AD  - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head 
      and Neck Cancer, First Hospital of Shanxi Medical University, 030001, Taiyuan, 
      Shanxi, P.R. China.
FAU - Bo, Yunfeng
AU  - Bo Y
AD  - Department of Pathology, Shanxi Cancer Hospital, 030013, Taiyuan, Shanxi, P.R. 
      China.
FAU - Dai, Fengsheng
AU  - Dai F
AD  - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital 
      of Shanxi Medical University, 030001, Taiyuan, Shanxi, P.R. China.
AD  - Department of Otolaryngology Head & Neck Surgery, First Hospital of Shanxi 
      Medical University, 030001, Taiyuan, Shanxi, P.R. China.
FAU - Lu, Yan
AU  - Lu Y
AD  - Department of Otolaryngology Head & Neck Surgery, First Affiliated Hospital of 
      Jinzhou Medical University, 121001, Jinzhou, Liaoning, P.R. China.
FAU - Yang, Dongli
AU  - Yang D
AD  - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital 
      of Shanxi Medical University, 030001, Taiyuan, Shanxi, P.R. China.
AD  - Department of Otolaryngology Head & Neck Surgery, First Hospital of Shanxi 
      Medical University, 030001, Taiyuan, Shanxi, P.R. China.
FAU - Guo, Yujia
AU  - Guo Y
AD  - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital 
      of Shanxi Medical University, 030001, Taiyuan, Shanxi, P.R. China.
AD  - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head 
      and Neck Cancer, First Hospital of Shanxi Medical University, 030001, Taiyuan, 
      Shanxi, P.R. China.
FAU - Guo, Huina
AU  - Guo H
AD  - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital 
      of Shanxi Medical University, 030001, Taiyuan, Shanxi, P.R. China.
AD  - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head 
      and Neck Cancer, First Hospital of Shanxi Medical University, 030001, Taiyuan, 
      Shanxi, P.R. China.
FAU - Li, Huizheng
AU  - Li H
AD  - Department of Otolaryngology Head & Neck Surgery, Dalian Municipal Friendship 
      Hospital, 116100, Dalian, Liaoning, P.R. China.
FAU - Zhang, Yu
AU  - Zhang Y
AD  - Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical 
      University, 030001, Taiyuan, Shanxi, P.R. China.
AD  - Department of Physiology, Shanxi Medical University, 030001, Taiyuan, Shanxi, 
      P.R. China.
FAU - Yang, Tao
AU  - Yang T
AD  - Department of Biochemistry & Molecular Biology, Shanxi Medical University, 
      030001, Taiyuan, Shanxi, P.R. China.
FAU - Li, Li
AU  - Li L
AD  - Department of Cell Biology and Genetics, Shanxi Medical University, 030001, 
      Taiyuan, Shanxi, P.R. China.
FAU - Zhang, Linshi
AU  - Zhang L
AD  - Department of Thyroid Surgery, Zhejiang University School of Medicine Second 
      Affiliated Hospital, 310009, Hangzhou, Zhejiang, P.R. China.
FAU - Hou, Rui
AU  - Hou R
AUID- ORCID: 0000-0001-6571-1514
AD  - Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for 
      Medical Research, University of Western Australia, Perth, WA, 6009, Australia.
FAU - Wen, Shuxin
AU  - Wen S
AUID- ORCID: 0000-0002-8377-2481
AD  - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head 
      and Neck Cancer, First Hospital of Shanxi Medical University, 030001, Taiyuan, 
      Shanxi, P.R. China. wensxsx@163.com.
AD  - Department of Otolaryngology Head & Neck Surgery, Shanxi Bethune Hospital, 
      030032, Taiyuan, Shanxi, P.R. China. wensxsx@163.com.
FAU - An, Changming
AU  - An C
AUID- ORCID: 0000-0002-8353-4547
AD  - Department of Head and Neck Surgery, Chinese Academy of Medical Sciences Cancer 
      Institute and Hospital, 100021, Beijing, P.R. China. anchangming@cicams.ac.cn.
FAU - Ma, Teng
AU  - Ma T
AUID- ORCID: 0000-0002-8360-1543
AD  - Department of Cellular and Molecular Biology, Beijing Tuberculosis and Thoracic 
      Tumor Research Institute, 101149, Beijing, P.R. China. mateng82913@163.com.
FAU - Jin, Lei
AU  - Jin L
AUID- ORCID: 0000-0001-7187-9671
AD  - School of Medicine and Public Health, The University of Newcastle, Callaghan, 
      NSW, 2308, Australia. lei.jin@newcastle.edu.au.
FAU - Xu, Wei
AU  - Xu W
AUID- ORCID: 0000-0002-9977-7535
AD  - Department of Head and Neck Surgery, Shandong Provincial ENT Hospital Affiliated 
      to Shandong University, 250022, Jinan, Shandong, P.R. China. xuwhns@126.com.
AD  - Shandong Provincial Institute of Otolaryngology, 250022, Jinan, Shandong, P.R. 
      China. xuwhns@126.com.
AD  - Key Laboratory of Otolaryngology, Ministry of Health, Shandong University, 
      250022, Jinan, Shandong, P.R. China. xuwhns@126.com.
FAU - Wu, Yongyan
AU  - Wu Y
AUID- ORCID: 0000-0003-1669-3860
AD  - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital 
      of Shanxi Medical University, 030001, Taiyuan, Shanxi, P.R. China. 
      wuyongyan@sxent.org.
AD  - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head 
      and Neck Cancer, First Hospital of Shanxi Medical University, 030001, Taiyuan, 
      Shanxi, P.R. China. wuyongyan@sxent.org.
AD  - Department of Otolaryngology Head & Neck Surgery, First Hospital of Shanxi 
      Medical University, 030001, Taiyuan, Shanxi, P.R. China. wuyongyan@sxent.org.
AD  - Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical 
      University, 030001, Taiyuan, Shanxi, P.R. China. wuyongyan@sxent.org.
AD  - Department of Biochemistry & Molecular Biology, Shanxi Medical University, 
      030001, Taiyuan, Shanxi, P.R. China. wuyongyan@sxent.org.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201026
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Ska3 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Animals
MH  - Biomarkers, Tumor/*metabolism
MH  - Cell Cycle Proteins/*metabolism
MH  - Cell Proliferation
MH  - Drug Resistance, Neoplasm
MH  - Glycolysis
MH  - Heterografts
MH  - Humans
MH  - Laryngeal Neoplasms/*drug therapy/genetics/metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, Nude
MH  - Microtubule-Associated Proteins/*metabolism
MH  - Molecular Targeted Therapy
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Signal Transduction
MH  - Squamous Cell Carcinoma of Head and Neck/*drug 
      therapy/genetics/metabolism/pathology
MH  - Polo-Like Kinase 1
PMC - PMC7589524
COIS- The authors declare that they have no conflict of interest.
EDAT- 2020/10/28 06:00
MHDA- 2021/05/18 06:00
PMCR- 2020/10/26
CRDT- 2020/10/27 05:42
PHST- 2020/08/24 00:00 [received]
PHST- 2020/10/06 00:00 [accepted]
PHST- 2020/10/04 00:00 [revised]
PHST- 2020/10/27 05:42 [entrez]
PHST- 2020/10/28 06:00 [pubmed]
PHST- 2021/05/18 06:00 [medline]
PHST- 2020/10/26 00:00 [pmc-release]
AID - 10.1038/s41419-020-03104-6 [pii]
AID - 3104 [pii]
AID - 10.1038/s41419-020-03104-6 [doi]
PST - epublish
SO  - Cell Death Dis. 2020 Oct 26;11(10):919. doi: 10.1038/s41419-020-03104-6.