PLEK2 promotes cancer stemness and tumorigenesis of head and neck squamous cell carcinoma via the c-Myc-mediated positive feedback loop

作     者：Xinyuan Zhao Dalong Shu Wenjuan Sun Shanshan Si Wei Ran Bing Guo Li Cui 

作者机构：Department of EndodonticsStomatological HospitalSouthern Medical UniversityGuangzhouGuangdong 510280P.R.China Department of Oral and Maxillofacial SurgeryThe First Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong 510080P.R.China Department of StomatologyThe Third Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong 510630P.R.China Department of Oral EmergencyStomatological HospitalSouthern Medical UniversityGuangzhouGuangdong 510280P.R.China Department of DentistryThe First Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong 510080P.R.China Department of Oral and Maxillofacial SurgeryStomatological HospitalSouthern Medical UniversityGuangzhouGuangdong 510280P.R.China Division of Oral Biology and MedicineSchool of DentistryUniversity of CaliforniaLos AngelesLos AngelesCalifornia 90095United States 

出 版 物：《Cancer Communications》 (癌症通讯（英文）)

年 卷 期：2022年第42卷第10期

页      面：987-1007页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：National Natural Science Foundation of China,Grant/Award Number:81901006 Guangdong Basic and Applied Basic Research Foundation,Grant/Award Number:2020A1515110051 Scientific Research Talent Cultivation Project of Stomatological Hospital,Southern Medical University,Grant/Award Number:RC202005 Science Research Cultivation Program of Stomatological Hospital,Southern Medical University,Grant/Award Number:PY2020002。 

主　　题：c-Myc cancer stemness FBXW7 HNSCC PLEK2 positive feedback loop tumorigenesis ubiquitination-mediated degradation 

摘      要：Background:Head and neck squamous cell carcinoma(HNSCC)is one of the most frequent malignancies worldwide and is characterized by unfavorable prognosis,high lymph node metastasis and early recurrence.However,the molecular events regulating HNSCC tumorigenesis remain poorly understood.Therefore,uncovering the underlying mechanisms is urgently needed to identify novel and promising therapeutic targets for HNSCC.In this study,we aimed to explore the role of pleckstrin-2(PLEK2)in regulating HNSCC tumorigenesis.Methods:The expression pattern of PLEK2 and its clinical significance in HNSCC were determined by analyzing publicly assessable datasets and our own independent HNSCC cohort.In vitro and in vivo experiments,including cell proliferation,colony formation,Matrigel invasion,tumor sphere formation,ALDEFLUOR,Western blotting assays and xenograft mouse models,were used to investigate the role of PLEK2 in regulating the malignant behaviors of HNSCC cells.The underlying molecular mechanisms for the tumor-promoting role of PLEK2 were elucidated using co-immunoprecipitation,cycloheximide chase analysis,ubiquitination assays,chromatin immunoprecipitation-quantitative polymerase chain reaction,luciferase reporter assays and rescue experiments.Results:The expression levels of PLEK2 mRNA and protein were significantly increased in HNSCC tissues,and PLEK2 overexpression was strongly associated with poor overall survival and therapeutic resistance.Additionally,PLEK2 was important for maintaining the proliferation,invasion,epithelial-mesenchymal transition,cancer stemness and tumorigenesis of HNSCC cells and could alter the cellular metabolism of the cancer cells.Mechanistically,PLEK2 interacted with c-Myc and reduced the association of F-box and WD repeat domain containing 7(FBXW7)with c-Myc,thereby avoiding ubiquitination and subsequent proteasome-mediated degradation of c-Myc.Moreover,the c-Myc signaling activated by PLEK2 was important for sustaining the aggressive malignant phenotypes and tumorigenesis of HNSCC cells.c-Myc also directly bounded to the PLEK2 promoter and activated its transcription,forming a positive feedback loop.Conclusions:Collectively,these findings uncover a previously unknown molecular basis of PLEK2-enhanced c-Myc signaling in HNSCC,suggesting that PLEK2 may represent a promising therapeutic target for treating HNSCC.