The high mobility group A1 (HMGA1) gene plays an important role in numerous malignant cancers. HMGA1 is an oncofoetal gene, and we have a certain understanding of the biological function of HMGA1 based on its activities in various neoplasms. As an architectural transcription factor, HMGA1 remodels the chromatin structure and promotes the interaction between transcriptional regulatory proteins and DNA in different cancers. Through analysis of the molecular mechanism of HMGA1 and clinical studies, emerging evidence indicates that HMGA1 promotes the occurrence and metastasis of cancer. Within a similar location or the same genetic background, the function and role of HMGA1 may have certain similarities. In this paper, to characterize HMGA1 comprehensively, research on various types of tumours is discussed to further understanding of the function and mechanism of HMGA1. The findings provide a more reliable basis for classifying HMGA1 function according to the tumour location. In this review, we summarize recent studies related to HMGA1, including its structure and oncogenic properties, its major functions in each cancer, its upstream and downstream regulation associated with the tumourigenesis and metastasis of cancer, and its potential as a biomarker for clinical diagnosis of cancer.

Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide, and metastasis is the principle reason for its poor prognosis. Overexpression of high-mobility gene group A2 (HMGA2) contributes to the aggressiveness of CRC. However, the underlying molecular mechanism of its overexpression is still elusive. In this study, we showed that ectopic expression of HMGA2 significantly enhanced cell migration and invasion in vitro and promoted tumor growth and distant metastasis in vivo . In contrast, the silencing of HMGA2 produced the opposite effects in vitro and in vivo . Chromatin immunoprecipitation-PCR and luciferase assays revealed that HMGA2 bound directly to the promoters of FN1 and IL11 and significantly induced their transcriptional activities. Moreover, as the direct downstream target of HMGA2, IL11 modulated cell migration and invasion through a pSTAT3-dependent signaling pathway. Furthermore, a strong positive correlation between HMGA2 and IL11 expression was identified in 122 CRC tissues. High IL11 expression was associated with poor differentiation, a large tumor size, lymph node metastasis and low overall survival in CRC patients. Collectively, our data reveal novel insights into the molecular mechanisms underlying HMGA2-mediated CRC metastasis and highlight the possibility of targeting HMGA2 and IL11 for treating CRC patients with metastasis.

Background: LOX-like 1 (LOXL1) is a lysyl oxidase, and emerging evidence has revealed its effect on malignant cancer progression. However, its role in colorectal cancer (CRC) and the underlying molecular mechanisms have not yet been elucidated. Methods: LOXL1 expression in colorectal cancer was detected by immunohistochemistry, western blotting and real-time PCR. In vitro, colony formation, wound healing, migration and invasion assays were performed to investigate the effects of LOXL1 on cell proliferation, migration and invasion. In vivo, metastasis models and mouse xenografts were used to assess tumorigenicity and metastasis ability. Molecular biology experiments were utilized to reveal the underlying mechanisms by which LOXL1 modulates the Hippo pathway. Results: LOXL1 was highly expressed in normal colon tissues compared with cancer tissues. In vitro, silencing LOXL1 in CRC cell lines dramatically enhanced migration, invasion, and colony formation, while overexpression of LOXL1 exerted the opposite effects. The results of the in vivo experiments demonstrated that the overexpression of LOXL1 in CRC cell lines drastically inhibited metastatic progression and tumour growth. Mechanistically, LOXL1 inhibited the transcriptional activity of Yes-associated protein (YAP) by interacting with MST1/2 and increasing the phosphorylation of MST1/2. Conclusions: LOXL1 may function as an important tumour suppressor in regulating tumour growth, invasion and metastasis via negative regulation of YAP activity. Graphical

The p53, a pivotal tumor suppressor, regulates various cellular responses, including DNA repair and apoptosis. Normally, p53 levels are low due to murine double minute clone 2 (MDM2) mediated polyubiquitination. However, stress signals disrupt p53-MDM2 interaction, stabilizing p53 and activating target genes. Dysfunctional p53 is common in cancers, especially colorectal cancer (CRC), with TP53 mutations in 43% of tumors. These mutations impair wild-type p53 function or confer novel activities, promoting cancer progression. Despite drugs targeting p53 entering trials, understanding wild-type and mutant p53 functions is crucial for novel CRC therapies. P53 mutations not only impact DNA repair and apoptosis but also play a crucial role in tumor immunotherapy. While rendering tumors resistant to chemotherapy, p53 mutations provide opportunities for immunotherapy due to neoantigen-rich tumors. Additionally, p53 mutations influence tumor microenvironment cells, such as fibroblasts and immunosuppressive cells, through p53-mediated signaling pathways. Investigating p53 mutations in tumor therapy is vital for personalized medicine and immunotherapy. In cancer treatment research, scientists explore drugs and strategies to restore or enhance p53 function. Targeting wild-type p53 aims to restore DNA repair and cell cycle control, while targeting mutant p53 seeks new drugs to inhibit its detrimental effects, advancing tumor treatment. Understanding p53 drugs and strategies is crucial for cancer therapy progress.

Yes-associated protein (YAP) is a central player in cancer development, with functions extending beyond its recognized role in cell growth regulation. Recent work has identified a link between YAP/transcriptional coactivator with PDZ-binding motif (TAZ) and the DNA damage response. Here, we investigated the mechanistic underpinnings of the cross-talk between DNA damage repair and YAP activity. Ku70, a key component of the nonhomologous end joining pathway to repair DNA damage, engaged in a dynamic competition with TEAD4 for binding to YAP, limiting the transcriptional activity of YAP. Depletion of Ku70 enhanced interaction between YAP and TEAD4 and boosted YAP transcriptional capacity. Consequently, Ku70 loss enhanced tumorigenesis in colon cancer and hepatocellular carcinoma (HCC) in vivo. YAP impeded DNA damage repair and elevated genome instability by inducing PARP1 degradation through the SMURF2-mediated ubiquitin-proteasome pathway. Analysis of samples from patients with HCC substantiated the link between Ku70 expression, YAP activity, PARP1 levels, and genome instability. In conclusion, this research provides insight into the mechanistic interactions between YAP and key regulators of DNA damage repair, highlighting the role of a Ku70-YAP-PARP1 axis in preserving genome stability. Significance: Increased yes-associated protein transcriptional activity stimulated by loss of Ku70 induces PARP1 degradation by upregulating SMURF2 to inhibit DNA damage, driving genome instability and tumorigenesis.