Background: The Makorin ring finger protein 1 (MKRN1) gene, also called RNF61, is located on the long arm of chromosome 7 and is a member of the RING finger protein family. The E3 ubiquitin ligase MKRN1 is closely linked to tumour development, but the exact mechanism needs to be elucidated. In this study, we aimed to investigate the specific mechanism and role of MKRN1 in colorectal cancer (CRC) development. Methods: MKRN1 expression in CRC was analysed using the Cancer Cell Line Encyclopaedia and the Cancer Genome Atlas (TCGA) databases. Rectal tumour tissues were frozen to explore the MKRN1 expression in CRC and its clinical significance. The impact of MKRN1 on CRC cell proliferation and migration was observed using CCK8, colony formation, wound healing, and transwell assays. A combination of MKRN1 quantitative proteomics, ubiquitination modification omics analysis, and a string of in vitro and in vivo experiments revealed the potential mechanisms by which MKRN1 regulates CRC metastasis. Results: MKRN1 expression was significantly elevated in CRC tissues compared to paracancerous tissues and was positively linked with prognosis (P < 0.01). MKRN1 downregulation inhibits CRC cell proliferation, migration, and invasion. Conversely, MKRN1 overexpression promotes the proliferation, migration, and invasion of CRC cells. Mechanistically, MKRN1 induces epithelial-mesenchymal transition (EMT) in CRC cells via ubiquitination and degradation of Smad nuclear-interacting protein 1 (SNIP1). Furthermore, SNIP1 inhibits transforming growth factor-β (TGF-β) signalling, and MKRN1 promotes TGF-β signalling by degrading SNIP1 to induce EMT in CRC cells. Finally, using conditional knockout mice, intestinal lesions and metastatic liver microlesions were greatly reduced in the intestinal knockout MKRN1 group compared to that in the control group. Conclusions: High MKRN1 levels promote TGF-β signalling through ubiquitination and degradation of SNIP1, thereby facilitating CRC metastasis, and supporting MKRN1 as a CRC pro-cancer factor. The MKRN1/SNIP1/TGF-β axis may be a potential therapeutic target in CRC.

Purpose: Numerous studies have emphasised the importance of necroptosis in the malignant progression of colorectal cancer (CRC). However, whether necroptosis-related genes (NRGs) can be used to predict the prognosis of CRC remains to be revealed. Methods: Patients with CRC were divided into two clusters based on the expression of NRGs, and prognosis was compared between the two clusters. A prognostic model was established based on NRGs, and its predictive efficiency was validated using Kaplan-Meier (K-M) curves, receiver operating characteristic (ROC) curves and a nomogram. Immune infiltration, single-cell and drug sensitivity analyses were used to examine the effects of NRGs on the prognosis of CRC. Results: The prognostic model served as a valid and independent predictor of CRC prognosis. Immune infiltration and single-cell analyses revealed that the unique immune microenvironment of CRC was regulated by NRGs. Drug sensitivity analysis showed that patients in the high- and low-risk groups were sensitive to different drugs. In addition, H2BC18 was found to play an important role in regulating the malignant progression of CRC. Conclusion: This study provides novel insights into precision immunotherapy based on NRGs in CRC. The NRG-based prognostic model may help to identify targeted drugs and develop more effective and individualised treatment strategies for patients with CRC.

Presented for the MKRN1 f/f group (IHC staining of TGF-β1) was inadvertently incorrect due to an oversight during figure preparation.

Multiple myeloma (MM) is a plasma cell malignancy prone to drug resistance, with unclear autophagy/apoptosis interactions in its etiology. This study explored transcription factor E4BP4's role in MM autophagy and apoptosis. Transcriptomic data from GEO and TCGA assessed E4BP4 expression and clinicopathological correlations. E4BP4 expression in MM cell line U266 and normal PBMCs was analyzed via western blotting, RT-qPCR, and immunohistochemistry. Autophagy/apoptosis markers were measured using CCK-8, flow cytometry, electron microscopy, and immunofluorescence. Molecular docking identified E4BP4 DNA-binding sites. Co-immunoprecipitation, luciferase reporter assays, and ChIP-qPCR analyzed E4BP4 transcriptional activity. E4BP4 knockdown effects were tested in mouse xenografts. E4BP4 was overexpressed in MM tumor tissues versus non-cancerous tissues, and in U266 cells versus PBMCs. High E4BP4 suppressed apoptosis and autophagy in MM cells. E4BP4 overexpression upregulated HDAC3 transcription, activated mTOR signaling, and reduced H3K9Ac/H3K27Ac association with Beclin1 promoter, decreasing Beclin1 expression. E4BP4 overexpression reduced U266 sensitivity to dexamethasone, while knockdown enhanced drug sensitivity. E4BP4 knockdown inhibited U266 xenograft growth in mice, with combined knockdown and dexamethasone yielding additive effects. E4BP4 promotes MM progression by upregulating HDAC3, reducing histone acetylation and Beclin1 transcription to suppress autophagy/apoptosis. Its role in dexamethasone resistance highlights E4BP4 as a potential therapeutic target.

Despite the emerging role of cuproptosis in cancer biology, the regulatory mechanism by which ubiquitination modulates this process through MKRN1 and SLC31