Sohlh2 promotes pulmonary fibrosis via repression of p62/Keap1/Nrf2 mediated anti-oxidative signaling pathway.

Disturbance in the redox balance of alveolar epithelial cells (AECs) was considered as a causal factor for pulmonary fibrosis. The regulatory mechanisms of redox hemostasis in the development of pulmonary fibrosis remain largely unknown. Using a type II AEC-specific Sohlh2 conditional knock-in (CKI) mouse model, we found that Sohlh2, a basic HLH transcription factor, accelerated age-related pulmonary fibrosis. High-fat diet (HFD) resulted in a tremendous increase in lung inflammation and fibrotic changes in the lung tissues of Sohlh2 CKI mice. Sohlh2 overexpression led to a significant rise of intracellular ROS and apoptosis in the lung, mouse primary AECIIs, and human A549 cells, which was attenuated by ROS inhibitor (NAC). Sohlh2 enhanced oxidative stress via repressing p62/Keap1/Nrf2 mediated anti-oxidative signaling pathway. p62, a direct target of Sohlh2, mediated Sohlh2 effects on ROS generation and apoptosis in A549 cells. Hence, our findings elucidate a pivotal mechanism underlying oxidative stress-induced pulmonary fibrosis, providing a framework for aging-related disorder interventions.

Sohlh2 Regulates the Stemness and Differentiation of Colon Cancer Stem Cells by Downregulating LncRNA-H19 Transcription.

Colon cancer stem cells (CSC) are tumor-initiating cells that drive tumorigenesis and progression through self-renewal and various differentiation potency. Therefore, the identification of factors critical for colon CSC function is vital for the development of therapies. Sohlh2 belongs to the superfamily of bhlh transcription factors and serves as a tumor suppressor in several tumors. The role of Sohlh2 in CSCs remains unknown. Here we demonstrated that Sohlh2 was related to the inhibition of LncRNA-H19/miR-141/ß-catenin signaling and led to the consequent suppression of colon CSC stemness and the promotion of colon CSC differentiation in vitro and in vivo. Moreover, Sohlh2 could directly bind to the promoter of LncRNA-H19 and repress its transcription activity. LncRNA-H19 mediated the effects of Sohlh2 on colon CSC stemness and differentiation. Clinically, we observed a significant inverse correlation between Sohlh2 and LncRNA-H19, ß-catenin, Lgr5, CD133 expression levels, and positive correlation between Sohlh2 and MUC2, TFF2 expression in colon cancer tissues. Collectively, our findings suggest an important role of the Sohlh2/LncRNA-H19/miR-141/ß-catenin pathway in regulating colon CSC stemness and differentiation, suggesting potential therapeutic targets for colon cancer. IMPLICATIONS: This study identifies that Sohlh2 directly manipulates LncRNA-H19 transcription and suppresses the ß-catenin signaling pathway and the Sohlh2/LncRNA-H19/miR-141/ß-catenin signaling pathway plays an essential role in the stemness of colon CSCs.

CHST4 might promote the malignancy of cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is reported as an aggressive cancer which leads to high mortality and no effective therapeutic target has yet been discovered. Surgical resection is the main method to treat patients with CCA. However, only one-third of CCA patients have the opportunity to accept the operation, leading to poor prognosis for CCA patients. Therefore, it is necessary to search for new therapeutic targets of CCA or core genes involved in the happening and growth of CCA. AIM: In this study, we utilized bioinformatics technology and accessed to several medical databases trying to find the core genes of CCA for the purpose of intervening CCA through figuring out an effective curative target. METHODS: Firstly, three differentially expressed genes (DEGs) were discovered from GEPIA, and by further observing the distribution and gene expression, CHST4 was obtained as the core gene. Afterwards, correlated genes of CHST4 in CCA were identified using UALCAN to construct a gene expression profile. We obtained PPI network by Search Tool for the Retrieval of Interacting Networks Genes (STRING) and screened core genes using cytoscape software. Functional enrichment analyses were carried out and the expression of CHST in human tissues and tumors was observed. Finally, a CCA model was established for qPCR and staining validation. RESULTS: Three differentially expressed genes (DEGs), CHST4, MBOAT4 and RP11-525K10.3, were obtained. All were more over-expressed in CCA samples than the normal, among which the change multiple and the gene expression difference of CHST4 was the most obvious. Therefore, CHST4 was selected as the core gene. We can see in our established protein-protein interaction (PPI) network that CHST4 had the highest degree of connectivity, demonstrating its close association with CCA. We found that genes were mainly enriched in CCs in the PPI networks genes which shows functional enrichment analysis results, including golgi lumen, extracellular space and extracellular region. CHST4 was found very specifically expressed in the bile duct and was significantly different from that in normal tissues. The overexpression of CHST4 was further verified in the established animal model of TAA-induced CCA in rats. Quantitative PCR (qPCR) demonstrated that CHST4 was significantly overexpressed in tumor tissues, verifying the role of CHST4 as the core gene of CCA. CONCLUSION: CHST4 was increasingly expressed in CCA and CHST4 is worth being studied much further in the intervention of CCA.

Sohlh2 Inhibits the Malignant Progression of Renal Cell Carcinoma by Upregulating Klotho via DNMT3a.

BACKGROUND: Renal cell carcinoma is the most common malignant tumor of the kidney. The 5-year survival of renal cell carcinoma with distant metastasis is very low. Sohlh2 is a newly discovered tumor suppressor gene playing inhibitory roles in a variety of tumors, but its role in renal cell carcinoma has not been reported. METHODS: To clarify the role of Sohlh2 in the occurrence and development of renal cell carcinoma, we constructed stably transfected human renal cell carcinoma cell lines with Sohlh2 overexpression and Sohlh2 knockdown, separately. First, we studied the effects of Sohlh2 on proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of renal cell carcinoma cells in vitro and in vivo. Then, we detected whether Sohlh2 functions through DNMT3a/Klotho using Western blotting, qPCR, and Cell Counting Kit-8 (CCK-8) assay. Finally, we collected 40 resected renal cell carcinoma samples to study the relevance between Sohlh2, DNMT3a, and Klotho by immunohistochemistry. RESULTS: Our results showed that Sohlh2 was downregulated in renal cell carcinoma, and its expression level was negatively correlated with tumor staging. Both in vitro and in vivo experiments confirmed that Sohlh2 overexpression inhibited the proliferation, migration, invasion, metastasis, and EMT of renal cell carcinoma. Sohlh2 functions through demethylation of Klotho by downregulating the expression of DNA methyltransferase of DNMT3a. In renal cell carcinoma, Sohlh2 was positively correlated with Klotho and negatively correlated with DNMT3a. CONCLUSION: Sohlh2 functions as a tumor suppressor gene in renal cell carcinoma by demethylation of Klotho via DNMT3a. Sohlh2 correlated with Klotho positively and with DNMT3a negatively in renal cell carcinoma. Our study suggests that Sohlh2 and DNMT3a/Klotho can be used as potential targets for the clinical treatment of renal cell carcinoma.