CHST7 Methylation Status Related to the Proliferation and Differentiation of Pituitary Adenomas

Wei Dong, Wenjian Shi, Yongliang Liu, Jingwu Li, Yu Zhang, Guilan Dong, Xiaoliu Dong, Hua Gao, Wei Dong, Wenjian Shi, Yongliang Liu, Jingwu Li, Yu Zhang, Guilan Dong, Xiaoliu Dong, Hua Gao

Abstract

Pituitary adenomas (PAs) are the second most common primary brain tumor and may develop from any of the cell lineages responsible for producing the different pituitary hormones. DNA methylation is one of the essential epigenetic mechanisms in cancers, including PAs. In this study, we measured the expression profile and promoter methylation status of carbohydrate sulfotransferase 7 (CHST7) in patients with PA; then, we investigated the effect of the CHST7 methylation status on the proliferation and differentiation of PAs. The volcano map and Metascape results showed that the levels of CHST7 were related to the lineages' differentiation and the cell adhesion of PAs, and patients with low CHST7 had greater chances of having an SF-1 lineage (p = 0.002) and optic chiasm compression (p = 0.007). Reactome pathway analysis revealed that most of the DEGs involved in the regulation of TP53 regulated the transcription of cell cycle genes (HSA-6791312 and HSA6804116) in patients with high CHST7. Correlation analysis showed that CHST7 was significantly correlated with the eIF2/ATF4 pathway and mitochondrion-related genes. The AUC of ROC showed that CHST7 (0.288; 95% CI: 0.187-0.388) was superior to SF-1 (0.555; 95% CI: 0.440-0.671) and inferior to FSHB (0.804; 95% CI: 0.704-0.903) in forecasting the SF-1 lineage (p < 0.001). The SF-1 lineage showed a higher methylation frequency for CHST7 than the Pit-1 and TBX19 lineages (p = 0.009). Furthermore, as the key molecule of the hypothalamic-pituitary-gonadal axis, inhibin βE (INHBE) was positively correlated with the levels of CHST7 (r = 0.685, p < 0.001). In summary, CHST7 is a novel pituitary gland specific protein in SF-1 lineage adenomas with a potential role in gonadotroph cell proliferation and lineage differentiation in PAs.

Trial registration: ClinicalTrials.gov NCT03271918 NCT00939523.

Keywords: CHST7; CHST71; DNA methylation; cell differentiation; cell proliferation; lineage; methylation; pituitary adenomas; tumor differentiation; tumor proliferation.

Conflict of interest statement

The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1
Figure 1
Differential gene enrichment analysis between different CHST7 groups. (A) Volcano plots showing the significantly differentially expressed genes. (B) GSEA employed to verify the signatures of the top 5 immunologic signature gene sets. (C) MetaScape enrichment analysis including pathways and GO terms.
Figure 2
Figure 2
Correlation analysis of CHST7 and EIF2 pathway. (A) Correlation of CHST7 and EIF2AK1-3. (B) Correlation of CHSTY and EIF2B1-3.
Figure 3
Figure 3
Western blot experiments of CHST7, POU1F1, DLL3, and EIF2AK3. (A) Electrophoretic band of CHST7, POU1F1, DLL3, and EIF2AK3 in 8 patients. (B) Correlation analysis of CHST7 and POU1F1, DLL3, and EIF2AK3. In this study, the gray value of patient 1 as 1.
Figure 4
Figure 4
The mRNA levels of CHST7, transcription factors, and receptors grouped by different CHST7-promoter-methylation statuses. (A) CHST7. (B) Pit-1. (C) TBX19. (D) SF-1. (E) ESR1. (F) ESR2. (G) SSTR2. (H) SSTR5. Compared to the hypermethylation group: * p < 0.05; ** p < 0.01; *** p < 0.001.
Figure 5
Figure 5
The mRNA levels of transcription factors and receptors compared with different mRNA levels of CHST7. (A) Pit-1; (B) TBX19; (C) SF-1; (D) ESR1; (E) ESR2; (F) SSTR2; (G) SSTR5. Compared to the low-CHST7 group: * p < 0.05; ** p < 0.01; *** p < 0.001.
Figure 6
Figure 6
CHST7 is related to the tumor differentiation of PAs. (A) Correlation analysis of CHST7 and Pit-1 in 106 samples. (B) Correlation analysis of CHST7 and SSTR2 in 106 samples. (C) ROC curve of CHST7 for the Pit-1 lineage. (D) ROC curve of CHST7 for the TBX19 lineage. (E) ROC curve of CHST7 for the SF-1 lineage.
Figure 7
Figure 7
INHBE is related to the tumor differentiation of PAs. (A) The correlation analysis of CHST7 and INHBC. (B) The correlation analysis of CHST7 and INHBE. (C) mRNA levels of INHBE in the three lineages. *** p < 0.001. (D) ROC curve of INHBE for the Pit-1 lineage. (E) ROC curve of INHBE for the TBX19 lineage. (F) ROC curve of INHBE for the SF-1 lineage.

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