QKI5-mediated alternative splicing of the histone variant macroH2A1 regulates gastric carcinogenesis.
Alternative pre-mRNA splicing is a key mechanism for increasing proteomic diversity and modulating gene expression. Emerging evidence indicated that the splicing program is frequently dysregulated during tumorigenesis. Cancer cells produce protein isoforms that can promote growth and survival. The RNA-binding protein QKI5 is a critical regulator of alternative splicing in expanding lists of primary human tumors and tumor cell lines. However, its biological role and regulatory mechanism are poorly defined in gastric cancer (GC) development and progression. In this study, we demonstrated that the downregulation of QKI5 was associated with pTNM stage and pM state of GC patients. Re-introduction of QKI5 could inhibit GC cell proliferation, migration, and invasion in vitro and in vivo, which might be due to the altered splicing pattern of macroH2A1 pre-mRNA, leading to the accumulation of macroH2A1.1 isoform. Furthermore, QKI5 could inhibit cyclin L1 expression via promoting macroH2A1.1 production. Thus, this study identified a novel regulatory axis involved in gastric tumorigenesis and provided a new strategy for GC therapy.
Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, PR China.|Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China.
Feng
F
Li
Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China.|Department of Obstetrics and Gynecology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, PR China.
Ping
P
Yi
Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China.
Jingnan
J
Pi
Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China.|Department of Obstetrics and Gynecology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, PR China.
Lanfang
L
Li
State Key Laboratory of Molecular Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China.
Jingyi
J
Hui
Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China.
Fang
F
Wang
Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, PR China.
Aihua
A
Liang
Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China.
Jia
J
Yu
D017398:Alternative Splicing; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D005260:Female; D064593:Heterografts; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D020033:Protein Isoforms; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C468873:CCNL1 protein, human; D016213:Cyclins; D006657:Histones; D020033:Protein Isoforms; D012322:RNA Precursors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C000620563:RNA-binding protein QKI-5, human; D025521:Tumor Suppressor Proteins
CCNL1; QKI5; alternative splicing; gastric cancer; macroH2A1