KIAA1429 contributes to liver cancer progression through N6-methyladenosine-dependent post-transcriptional modification of GATA3
Authors: Hui Li
Tian Lan
Mingheng Liao
Kefei Yuan
Jiwei Huang
Yong Zeng
Xiangyong Hao
Lin Xu
Xiaokai Yan
Haotian Liao
Xiangzheng Chen
Jiaxin Li
Hailing Liu
Delin Zhang
Kunlin Xie
Hong Wu
Journal: Molecular cancer (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: GATA3; GATA3-AS; Hepatocellular carcinoma; KIAA1429; N6-methyladenosine.
Affiliations: Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China., Department of Hepatobiliary Surgery, Guizhou Provincial People's Hospital, Guiyang, 550002, China., Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China., Department of General Surgery, Gansu Provincial Hospital, Lanzhou, 730000, China., Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. ., Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. .

Abstract:  Background: N6-methyladenosine (m6A) modification, the most abundant internal methylation of eukaryotic RNA transcripts, is critically implicated in RNA processing. As the largest known component in the m6A methyltransferase complex, KIAA1429 plays a vital role in m6A methylation. However, its function and mechanism in hepatocellular carcinoma (HCC) remain poorly defined. Methods: Quantitative PCR, western blot and immunohistochemistry were used to measure the expression of KIAA1429 in HCC. The effects of KIAA1429 on the malignant phenotypes of hepatoma cells were examined in vitro and in vivo. MeRIP-seq, RIP-seq and RNA-seq were performed to identify the target genes of KIAA1429. Results: KIAA1429 was considerably upregulated in HCC tissues. High expression of KIAA1429 was associated with poor prognosis among HCC patients. Silencing KIAA1429 suppressed cell proliferation and metastasis in vitro and in vivo. GATA3 was identified as the direct downstream target of KIAA1429-mediated m6A modification. KIAA1429 induced m6A methylation on the 3' UTR of GATA3 pre-mRNA, leading to the separation of the RNA-binding protein HuR and the degradation of GATA3 pre-mRNA. Strikingly, a long noncoding RNA (lncRNA) GATA3-AS, transcribed from the antisense strand of the GATA3 gene, functioned as a cis-acting element for the preferential interaction of KIAA1429 with GATA3 pre-mRNA. Accordingly, we found that the tumor growth and metastasis driven by KIAA1429 or GATA3-AS were mediated by GATA3. Conclusion: Our study proposed a complex KIAA1429-GATA3 regulatory model based on m6A modification and provided insights into the epi-transcriptomic dysregulation in hepatocarcinogenesis and metastasis. 

Retracted: No

PubPeer comments:
 Questions to the authors: Figure 1f and g: Why do the flow cytometry dot plots have axis which goes from 0 to 10000 and then 100000 and so on. I would expect to see it on the cell distribution. Figure 2g and h: Two of the mice look very similar with a characteristic black mark at the back (marked with a yellow circle here), but they represent different treatment. Why? ![file] , 
 Thank you so much for your attention to our work. In terms of Figure 1f and g, the flow cytometry apoptosis was performed on cytoflex. The data were automatically exported. As for the axis, you can see a cluster of ticks straight after tick zero, which ranged from 0 to 1000. However, that was not enough clear due to a low resolution level. The more clear figures were attached. ![file] ![file] As for Figure 2g and h, the mice with characteristic black mark at the back were purchased from Model Animal Research Center of Nanjing University, because the mice provided by BEIJING HFK BIOSCIENCE CO., LTD was not enough. Therefore, some mice were labelled with black marks at the backs to differentiate between the two institutions. These mice look very similar, because of a low resolution level. In fact, they were totally different. The more clear figures were attached. ![file] ![file] You can see that these two mice were totally different in both marks and appearances. Thank you again for your kind attention. ,