Abstract
Our recent studies have indicated that specificity protein-1 (Sp1) accumulates substantially in the early stage of lung cancer but is partially decreased in the late stages, which is an important factor in the progression of the cancer. In this study, we found that Nm23-H1 and hnRNPA2/B1 could be recruited to the 5′UTR of Sp1 mRNA. In investigating the clinical relevance of Nm23-H1/Sp1 levels, we found a positive correlation between lung cancer patients with poor prognosis and low levels of Sp1 and Nm23-H1, suggesting an association between Nm23-H1/Sp1 levels and survival rate. Knockdown of Nm23-H1 inhibits lung cancer growth but increases lung cancer cell malignancy, which could be rescued by overexpression of Sp1, indicating that Nm23-H1-induced Sp1 expression is critical for lung cancer progression. We also found that Nm23-H1 increases the protein stability of hnRNPA2/B1and is thereby co-recruited to the 5′UTR of Sp1 mRNA to regulate cap-independent translational activity. Since the Sp1 level is tightly regulated during lung cancer progression, understanding the molecular mechanisms underlying the regulation by Nm23-H1/hnRNPA2B1 of Sp1 expression in the various stages of lung cancer will be beneficial for lung cancer therapy in the future.
Highlights
Specificity protein-1 (Sp1) belongs to the specificity protein/Krüppel-like factor (SP/KLF) transcription factor family, and is expressed in mammalian cells[1]
The data indicated that there was no significant difference in the mRNA levels between normal and lung cancer patients, implying that other mechanism(s), such as protein stability or translational activity, might be crucial for the regulation of specificity protein-1 (Sp1) during lung cancer progression
The results showed that hnRNPA2/B1 and Nm23-H1 bound to the 5′UTR of Sp1 mRNA (Fig. 1A)
Summary
Specificity protein-1 (Sp1) belongs to the specificity protein/Krüppel-like factor (SP/KLF) transcription factor family, and is expressed in mammalian cells[1]. Previous analyses have suggested that transcriptional activity, translational efficacy, and protein stability all contribute to the regulation of Sp1 levels in lung cancer development, indicating that multiple strategies are utilized to control the level of Sp1 during cancer formation[4, 6,7,8]. Recent studies have demonstrated that analysis of Nm23-dependent gene expression is a valid approach for identifying potential modulators of metastatic potential in several cancer types. Nm23-H1 has been suggested to be an anti-metastasis marker in different cancer types and its expression is related to patient survival. HnRNPA2/B1 includes two alternative splicing variants-A2 and B1-and belongs to a family of RNA-binding proteins involved in the regulation of gene expression at the transcriptional and translational stages[16]. We found that the Nm23-H1/ hnRNPA2/B1/Sp1 axis might be important for controlling lung cancer progression
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