TWIST1 x YY1

Double homeobox A pseudogene 9 (DUXAP9), also known as long intergenic non-coding RNA 1296 (LINC01296) and lymph node metastasis-associated transcript 1 (LNMAT1), is an emerging lncRNA encoded by a pseudogene. It has been reported to be upregulated in various tumor types and functions as an oncogenic factor. The high expression of DUXAP9 is closely related to clinical pathological features and poor prognosis in 16 types of malignant tumors. DUXAP9 is transcriptionally activated by YY-1 and Twist1 and functions as a guide or scaffold for biomolecular complexes and chromatin modifiers, or as a "decoy" for miRNAs, mRNAs, and proteins, thereby regulating gene expression. Moreover, the PI3K/AKT, NF-κB, MAPK/ERK, and Wnt/β- catenin signaling pathways are variously activated or inhibited by DUXAP9, subsequently influencing the biological behaviors of tumor cells, including proliferation, apoptosis, cell cycle arrest, migration, invasion, epithelial-mesenchymal transition (EMT), and drug resistance. This review summarizes recent research on DUXAP9 in oncology, offering insights into its expression characteristics, biological functions, molecular mechanisms, and clinical significance for cancer diagnosis, treatment, and prognosis.

Rotator cuff injuries present significant clinical challenges, often resulting in chronic pain and functional impairment. In this study, we examined the effects of hyperlipidemia (HYP), a systemic metabolic condition, on tendon health. Histological analysis of infraspinatus tendons from hyperlipidemic swine revealed well-organized extracellular matrix (ECM) structures, comparable to those in non-hyperlipidemic (NONHYP) animals, suggesting ECM reorganization. Upstream SIGNOR3.0 analysis demonstrated that tumor necrosis factor receptor-associated factor 6 (TRAF6) activates transcription factor Yin Yang 1 (YY1) via kinase signaling, underscoring its role in tendon ECM remodeling. Hence, we futher examined the role of YY1, which is a critical regulator of collagen synthesis identified through network analysis. Although TRAF6 levels remained unchanged in HYP conditions, increased YY1 expression correlated with elevated COL1 gene expression. Additionally, twist-related protein 1 (TWIST1) emerged as another key molecule, existing in both homo- and heterodimer forms in NON-HYP conditions, but only as a heterodimer in HYP. YY1 enhanced COL1 transcription in the hyperlipidemic environment, while TWIST1 heterodimer formation facilitated collagen crosslinking. Notably, increased YY1 expression inhibited MMP3, resulting in the inactivity of MMP1, MMP8, and MMP9, thereby preserving collagen levels. These findings highlight the complex molecular interactions involving transcriptional regulation by YY1 and post-translational regulation by the TWIST1 heterodimer, essential for the deposition of mature collagen fibrils and driving tendon remodeling in hyperlipidemic conditions. This study offers valuable insights for the change of tendon health condition in hyperlipidemia disease or tendon pathology.

Hepatocellular carcinoma (HCC) is one of the leading causes of death, which deserves further study to reveal the underlying molecular mechanisms. Studies have shown that miR-9 in associated with poor prognosis in HCC patients. However, the mechanisms of transcriptional activation regulation of miR-9 and its role in the malignant progression of HCC have been rarely investigated. Some transcriptional coactivators can form phase-separated condensates at super-enhancers that compartmentalize and concentrate the transcription apparatus to drive robust gene expression. Here, we demonstrate that Twist1 and YY1 could form a transcriptional complex with p300, creating local high-concentration phase-separated interaction hubs at the super-enhancers of miR-9 and activate its expression to promote the malignant progression of HCC by stimulating the migration and invasion of hepatocellular carcinoma cells. Twist1-YY1-p300 phase-separated condensates were disrupted by metformin (Met) and thus reduce miR-9 expression, thereby inhibiting the malignant progression of HCC. Our study demonstrates that the Twist1 transcriptional factor complex involved in the malignant progression of HCC can form phase separation condensates at super-enhancers of miR-9 to promote the expression of oncogenes in HCC cells. It provides a potential target for the therapy of HCC and offers insights into the mechanism of Met in HCC inhibition.