Open AccessThe Nedd8‐activating enzyme inhibitor MLN 4924 ( TAK ‐924/Pevonedistat) induces apoptosis via c‐Myc‐Noxa axis in head and neck squamous cell carcinoma
Author(s) -
Zhang Wenjuan,
Liang Yupei,
Li Lihui,
Wang Xiaofang,
Yan Zi,
Dong Changsheng,
Zeng MuSheng,
Zhong Qian,
Liu XueKui,
Yu Jinha,
Sun Shuyang,
Liu Xiaojun,
Kang Jihui,
Zhao Hu,
Jeong Lak Shin,
Zhang Yanmei,
Jia Lijun
Publication year - 2019
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/cpr.12536
Subject(s) - neddylation , propidium iodide , nedd8 , head and neck squamous cell carcinoma , annexin , cancer research , apoptosis , biology , ubiquitin , chemistry , programmed cell death , cancer , ubiquitin ligase , biochemistry , genetics , head and neck cancer , gene
Objectives The present study aimed to reveal expression status of the neddylation enzymes in HNSCC and to elucidate the anticancer efficacy and the underlying mechanisms of inhibiting neddylation pathway. Materials and methods The expression levels of neddylation enzymes were estimated by Western blotting in human HNSCC specimens and bioinformatics analysis of the cancer genome atlas ( TCGA ) database. Cell apoptosis was evaluated by Annexin V fluorescein isothiocyanate/propidium iodide (Annexin V‐ FITC / PI ) stain and fluorescence‐activated cell sorting ( FACS ). Small interfering RNA (si RNA ) and the CRISPR ‐Cas9 system were used to elucidate the underlying molecular mechanism of MLN 4924‐induced HNSCC apoptosis. Results Expression levels of NAE 1 and UBC 12 were prominently higher in HNSCC tissues than that in normal tissues. Inactivation of the neddylation pathway significantly inhibited malignant phenotypes of HNSCC cells. Mechanistic studies revealed that MLN 4924 induced the accumulation of CRL ligase substrate c‐Myc that transcriptionally activated pro‐apoptotic protein Noxa, which triggered apoptosis in HNSCC . Conclusions These findings determined the over‐expression levels of neddylation enzymes in HNSCC and revealed novel mechanisms underlying neddylation inhibition induced growth suppression in HNSCC cells, which provided preclinical evidence for further clinical evaluation of neddylation inhibitors (eg, MLN 4924) for the treatment of HNSCC .