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O-GlcNAcylation of SIX1 enhances its stability and promotes Hepatocellular Carcinoma Proliferation.

ABSTRACT: It is universally accepted that aberrant metabolism facilitates tumor growth. However, how cancer cells coordinate glucose metabolism and tumor proliferation is largely unknown. Sine oculis homeobox homolog 1 (SIX1) is a transcription factor that belongs to the SIX family and is believed to play an important role in the regulation of the Warburg effect in tumors. However, whether the role of SIX1 and the molecular mechanisms that regulate its activity are similar in hepatocellular carcinoma (HCC) still needs further investigation. Methods: Western blotting was performed to determine the levels of SIX1 and O-linked ?-N-acetylglucosaminylation (O-GlcNAcylation) in HCC tissues. Cell Counting Kit 8 (CCK8), colony formation and mouse tumor model assays were used to establish the role of SIX1 and O-GlcNAcylation in HCC processes. Mass spectrometry, immunoprecipitation and site-directed mutagenesis were performed to confirm the O-GlcNAcylation of SIX1. Results: Here, we demonstrated that SIX1, the key transcription factor regulating the Warburg effect in cancer, promotes HCC growth in vitro and in vivo. Furthermore, we revealed that SIX1 could also enhance the levels of a posttranslational modification called O-GlcNAcylation. Importantly, we found that SIX1 was also highly modified by O-GlcNAcylation and that O-GlcNAcylation inhibited the ubiquitination degradation of SIX1. In addition, site-directed mutagenesis at position 276 (T276A) decreased the O-GlcNAcylation level and reversed the protumor effect of SIX1. Conclusions: We conclude that O-GlcNAcylation of SIX1 enhances its stability and promotes HCC proliferation. Our findings illustrate a novel feedback loop of SIX1 and O-GlcNAcylation and show that O-GlcNAcylation of SIX1 is an important way to coordinate glucose metabolism and tumor progression.

SUBMITTER: Chu Y

PROVIDER: S-EPMC7449927 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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O-GlcNAcylation of SIX1 enhances its stability and promotes Hepatocellular Carcinoma Proliferation.

Chu Yi Y Jiang Mingzuo M Wu Nan N Xu Bing B Li Wenjiao W Liu Haiming H Su Song S Shi Yanting Y Liu Hao H Gao Xiaoliang X Fu Xin X Chen Di D Li Xiaowei X Wang Weijie W Liang Jie J Nie Yongzhan Y Fan Daiming D

Theranostics 20200802 21

It is universally accepted that aberrant metabolism facilitates tumor growth. However, how cancer cells coordinate glucose metabolism and tumor proliferation is largely unknown. Sine oculis homeobox homolog 1 (SIX1) is a transcription factor that belongs to the SIX family and is believed to play an important role in the regulation of the Warburg effect in tumors. However, whether the role of SIX1 and the molecular mechanisms that regulate its activity are similar in hepatocellular carcinoma (HCC ...[more]

PMID: 32863962

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Project description:Fewer than 30% of patients with hepatocellular carcinoma (HCC) are eligible to receive curative therapies, and so a better understanding of the molecular mechanisms of HCC is needed to identify potential therapeutic targets. The role of microRNA (miRNA) in modulating tumour progression has been demonstrated, and therapies targeting miRNA appear promising. miR-204-5p has been shown to function in numerous types of cancer, but its role in HCC remains unclear. In this study, we found that miR-204-5p expression was downregulated in cancerous HCC tissues compared to nontumour tissues. Kaplan-Meier survival curve analysis also showed that low expression of miR-204-5p predicted worse outcomes of HCC patients. In addition, miR-204-5p expression was significantly lower in HCC cell lines. The function of miR-204-5p was also assessed both in vitro and in vivo. We demonstrated that ectopic expression of miR-204-5p in HCC cell lines inhibited HCC cell proliferation and clonogenicity using CCK8, BrdU and colony-forming assays, while the inhibition of miR-204-5p enhanced proliferation and clonogenicity. Further in vivo studies in mice further confirmed the proliferation capacity of miR-204-5p. We also identified sine oculis homeobox homologue 1 (SIX1) as a direct target of miR-204-5p and showed that it was inversely correlated with miR-204-5p in both human and mouse HCC tissues. Transfection of miR-204-5p mimics in BEL-7404 cells blocked the cell cycle by inhibiting the expression of cyclin-D1 and cyclin-A1, cell cycle-related factors regulated by SIX1. More importantly, overexpression of the 3'UTR mutant SIX1 but not the wild-type SIX1 abolished the suppressive effect of miR-204-5p, and downregulated SIX1 in BEL-7402 cells that transfected with miR-204 inhibitors could partly block the inhibitory effect of miR-204-5p on proliferation. Thus, we have demonstrated that miR-204-5p suppresses HCC proliferation by directly regulating SIX1 and its downstream factors.

Dataset Information

O-GlcNAcylation of SIX1 enhances its stability and promotes Hepatocellular Carcinoma Proliferation.

Publications

O-GlcNAcylation of SIX1 enhances its stability and promotes Hepatocellular Carcinoma Proliferation.

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