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Shaomei Tang,1,* Xiaoliang Huang,2,* Xi Wang,3,* Xianguo Zhou,4 Huan Huang,3 Liwen Qin,3 Hongyu Tao,3 Qiuyan Wang,3– 5 Yuting Tao3,6 1The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 2Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of China; 3Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 4Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of China; 5Guangxi Colleges and Universities Key Laboratory of Biological Molecular Medicine Research, Nanning, Guangxi, People’s Republic of China; 6Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi, Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, Guangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuting Tao; Qiuyan WangCenter for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, People’s Republic of ChinaEmail tytxzxh@126.com; qiuyanwang510@yahoo.comPurpose: H2A.Z is an oncogenic histone variant that is overexpressed in cancers. Two isoforms of H2A.Z, H2AFZ and H2AFV, are identical except for a three-amino acid difference. However, their isoform-specific functions remain unclear in cancer development. Thereby, this study aimed to investigate whether the two isoforms play distinct functions in hepatocarcinogenesis.Materials and Methods: Expressions of H2A.Z isoforms in 116 paired hepatocellular cancerous and para-cancerous tissues were detected by employing qPCR. GEO and TCGA databases were used to probe expressions and prognostic value of the two H2A.Z isoforms. A comprehensive meta-analysis was conducted. Furthermore, co-expressed analysis of H2AFZ and H2AFV was performed by using cBioPortal database. H2A.Z binding genes from Chip-seq were intersected with H2A.Z isoforms co-expressed genes to perform functional annotations. Cell proliferation experiments from H2AFZ knockout HepG2 and BEL-7402 cells were implemented. Finally, RNA-seq was applied to analyse alternative splicing in H2AFZ knockout and wild-type cells.Results: H2AFZ and H2AFV were both significantly upregulated (P < 0.01) in hepatocellular carcinoma and related to poor prognosis (P < 0.01). The two H2A.Z isoforms played vital roles in cell proliferation. It is also predicted that unique functions of H2AFV contain spindle midzone and microtubule, while H2AFZ is especially associated with RNA export and spliceosome. Further, devoid H2AFZ may restrain liver cancer cell proliferation and cause many alternative splicing events.Conclusion: Both H2A.Z isoforms play vital and distinct roles in the occurrence and progression of liver cancer, which may pave a way for novel therapeutic applications for cancers in the future.Keywords: H2A.Z, H2AFV, H2AFZ, hepatocellular carcinoma, functional annotations, distinct roles