P4HA1 (Prolyl 4-Hydroxylase Subunit Alpha 1)

Our findings elucidate the importance of the P4HA1-P4HA2-PI3K-AKT axis in CRC and identify P4HA1 as a promising therapeutic target to impede CRC growth and metastasis while altering the tumor immune landscape. This research provides a foundation for further investigations into P4HA1-targeted therapies, which may improve clinical outcomes for patients with CRC.

In xenografts model, P4HA1 knockdown effectively suppressed tumor malignant progress, confirming that P4HA1 was positive correlation with SPP1 + TAMs and could mediate tumor hypoxia pathways. Overall, this study identified P4HA1 as a key gene involved in regulating SPP1 + TAMs through modulating hypoxia, providing a potential macrophage-centered therapeutic target in HNSCC.

Additionally, the results suggest the mutational status of the KRAS gene did not significantly affect the expression of any of the validated genes, indicating that these genes are not involved in the carcinogenesis of KRAS-mutated CRC. Based on our results, the genes P4HA1 and SPP1 appear to play a role in the progression and metastasis of colorectal cancer and are candidate genes for further investigation as potential biomarkers in CRC.

Characterization of P4HA1 overexpression has demonstrated links to key hallmarks of cancer, not only in the canonical collagen deposition role, but also in non-canonical functions, such as cell stemness, hypoxic response, glucose metabolism, angiogenesis, and modulation of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment. P4HA1 is thus an attractive target for developing novel targeted therapies to improve treatment response in many cancer types.

We verified these findings through multiple approaches, including in silico validation using multiple external datasets as well as experimental validation. Given that the loss of P4HA1 may disrupt stem cell development and inflammation response, our results suggest that targeting P4HA1 may offer a promising therapeutic strategy for breast cancer treatment.

Furthermore, hydroxyproline promotes the proliferation and migration of hESCs. These findings provide new insights into the pathogenesis of adenomyosis and suggest potential therapeutic strategies.

To further interrogate the role of P4HA1 in invasion of hypoxic patient-derived organoids, we quantified invasion in organoids modified to knockdown and or overexpress P4HA1, demonstrating that P4HA1 is necessary for hypoxia-enhanced invasion and sufficient to increase invasion in normoxia in PDAC organoids. Our results identify P4HA1 as a driver of PDAC organoid invasion in hypoxia.

The study concluded that P4HA1 has the potential to be expressed substantially in GC tissues and cells and is capable of enhancing the proliferation, metastasis, and stemness of GC.

Given the crucial roles of USP10 in HCC progression, we further validated ginkgolic acid, a hit compound that targets USP10, leading to potential anti-HCC efficacy in xenograft mouse models. Overall, our study provides novel insights into the role and potential molecular mechanisms of USP10 on proline metabolism in HCC for the first time, as well as offers a promising therapeutic strategy of targeting USP10 for HCC treatment.

Our findings highlight the interplay between glycolysis and immune cell infiltration in disease prognosis. This model provides insights for targeted therapies and a foundation for further research into osteosarcoma treatment.

These results reveal a novel hypoxia-induced HIF1ɑ-ATF3-P4HA1 axis which can potentially be exploited as a therapeutic target to impede EMT and ultimately breast cancer invasion. Hypoxia induced ATF3 regulates P4HA1 expression and alternative splicing to promote breast cancer invasion.

Together, our study demonstrates that HIF1α/ATF3 participated in P4HA1/succinate signaling, which is the major regulator of succinate biosynthesis and PGK1 succinylation at K191 and K192 sites in GBM. The P4HA1/succinate pathway might be a novel and promising target for aerobic glycolysis in GBM.