TP53INP2 modulates the malignant progression of colorectal cancer by reducing the inactive form of ß-catenin.

TP53INP2 (tumor protein p53-inducible nuclear protein 2), known as an autophagy protein, is essential for regulating transcription and starvation-induced autophagy, which plays a crucial role in the oncogenesis and progression of various cancers. The present study aims to investigate the expression pattern, function and prognostic value of TP53INP2 in colorectal cancer (CRC). Here, we report that low expression of TP53INP2 correlates with poor survival in CRC patients. TP53INP2 was significantly downregulated in CRC tissues compared with adjacent tissues. As the malignancy of CRC progresses, the expression level of TP53INP2 gradually decreased. Knockdown of TP53INP2 promoted CRC cell proliferation and tumor growth in mice. Mechanistically, TP53INP2 deficiency decreased phosphorylation of ß-catenin on S33, S37, and T41, resulting in increased accumulation of ß-catenin and enhanced nuclear translocation and transcriptional activity. Moreover, we further demonstrated that TP53INP2 sequestered TIM50, thereby inhibiting its activation of ß-catenin. Taken together, our findings indicate that the downregulation of TP53INP2 promotes CRC progression by activating ß-catenin and suggest that TP53INP2 may be a candidate therapeutic target for CRC.

G-quadruplex structures in FGFR3 promoter negatively regulate its gene expression and DNA replication.

FGFR3 activating mutations and abnormal expression are linked to tumor development. However, the current state of research on FGFR3 gene expression regulation is relatively insufficient. In this study, we have reported that the FGFR3 promoter's positive strand contains several G-tracts and most likely forms a G-quadruplex (G4) structure. Circular dichroism investigations revealed that oligonucleotides from this region exhibit G-quadruplex-like molar ellipticity. We further validated the G4 structure of the FGFR3 promoter using biochemical and cellular molecular biology techniques. The G-quadruplex mutation enhanced the transcriptional activity of the FGFR3 promoter and DNA replication, suggesting that the G4 structure inhibits its expression. Furthermore, we conducted a preliminary screen for helicases associated with FGFR3 expression and explored their regulatory effects on FGFR3 gene transcription. Subsequently, we investigated the effect of curcumin on the stability of the G4 structure of the FGFR3 promoter and its regulatory effect on FGFR3 expression.

Mechanisms regulating DMTF1ß/γ expression and their functional interplay with DMTF1α.

The cyclin D binding myb­like transcription factor 1 (DMTF1), a haplo­insufficient tumor suppressor gene, has 3 alternatively spliced mRNA isoforms encoding DMTF1α, ß and γ proteins. Previous studies have indicated a tumor suppressive role of DMTF1α and the oncogenic activity of DMTF1ß, while the function of DMTF1γ remains largely undetermined. In the present study, the mechanisms regulating DMTF1 isoform expression were investigated and the functional interplay of DMTF1ß and γ with DMTF1α was characterized. It was found that specific regions of DMTF1ß and γ transcripts can impair their mRNA integrity or stability, and thus reduce protein expression levels. Additionally, DMTF1ß and γ proteins exhibited a reduced stability compared to DMTF1α and all 3 DMTF1 isoforms were localized in the nuclei. Two basic residues, K52 and R53, in the DMTF1 isoforms determined their nuclear localization. Importantly, both DMTF1ß and γ could associate with DMTF1α and antagonize its transactivation of the ARF promoter. Consistently, the ratios of both DMTF1ß/α and γ/α were significantly associated with a poor prognoses of breast cancer patients, suggesting oncogenic roles of DMTF1ß and γ isoforms in breast cancer development.

Functional analysis of YY1 zinc fingers through cysteine mutagenesis.

As a transcription factor, Yin Yang 1 (YY1) either activates or represses gene expression depending on its recruited cofactors. The YY1 C-terminal consists of four zinc fingers (ZF) that are responsible for its DNA binding. However, the contribution of each YY1 ZF to its functions have not been fully elucidated. In this study, we used alanines to replace YY1 cysteines that are crucial to ZFs in binding to DNA. We characterized these YY1 mutants for their DNA binding, transcriptional activity, and functional role in maintaining MDA-MB-231 cell proliferation. We demonstrated that ZFs 2 and 3 are essential to the general biological activity of YY1. ZF 1 showed relatively low importance, while ZF 4 is virtually dispensable for YY1 function.