Background: Triple-negative breast cancer (TNBC) remains the most challenging subtype of breast cancer and lacks definite treatment targets. Aerobic glycolysis is a hallmark of metabolic reprogramming that contributes to cancer progression. PFKP is a rate-limiting enzyme involved in aerobic glycolysis, which is overexpressed in various types of cancers. However, the underlying mechanisms and roles of the posttranslational modification of PFKP in TNBC remain unknown. Methods: To explore whether PFKP protein has a potential role in the progression of TNBC, protein levels of PFKP in TNBC and normal breast tissues were examined by CPTAC database analysis, immunohistochemistry staining (IHC), and western blotting assay. Further CCK-8 assay, colony formation assay, EDU incorporation assay, and tumor xenograft experiments were used to detect the effect of PFKP on TNBC progression. To clarify the role of the USP5-PFKP pathway in TNBC progression, ubiquitin assay, co-immunoprecipitation (Co-IP), mass spectrometry-based protein identification, western blotting assay, immunofluorescence microscopy, in vitro binding assay, and glycolysis assay were conducted. Results: Herein, we showed that PFKP protein was highly expressed in TNBC, which was associated with TNBC progression and poor prognosis of patients. In addition, we demonstrated that PFKP depletion significantly inhibited the TNBC progression in vitro and in vivo. Importantly, we identified that PFKP was a bona fide target of deubiquitinase USP5, and the USP5-mediated deubiquitination and stabilization of PFKP were essential for cancer cell aerobic glycolysis and TNBC progression. Moreover, we found a strong positive correlation between the expression of USP5 and PFKP in TNBC samples. Notably, the high expression of USP5 and PFKP was significantly correlated with poor clinical outcomes. Conclusions: Our study established the USP5-PFKP axis as an important regulatory mechanism of TNBC progression and provided a rationale for future therapeutic interventions in the treatment of TNBC.

Glioma is a highly aggressive brain tumor with limited treatment success due to its resistance to conventional therapies. Sirtuin 5 (SIRT5) has emerged as a promising target for cancer therapy, though it exhibits dual roles in different cancer types. In this study, we investigate the role of SIRT5 in glioma and its corresponding mechanisms. Our findings demonstrate that SIRT5 expression is elevated in glioma cells both in vitro and in vivo. SIRT5 knockdown significantly reduced glioma cell proliferation and enhanced sensitivity to ferroptosis. Proteomic and metabolomic analyses identifies branched-chain amino acid (BCAA) metabolism as a key downstream pathway regulated by SIRT5 through branched-chain aminotransferase 1 (BCAT1). Specifically, SIRT5-mediated desuccinylation of BCAT1 at K39 inhibits its interaction with the E3 ligase CHIP, thereby preventing BCAT1 degradation via the ubiquitin-proteasome system. Moreover, BCAT1 overexpression reverses the proliferation inhibition and ferroptosis sensitivity observed in SIRT5-knockdown cells. Clinically, we reveal a positive correlation between SIRT5 and BCAT1 levels in glioma samples, with higher expression levels predicting more advanced glioma grades and poorer clinical outcomes. Collectively, this study highlights the critical role of SIRT5 in promoting glioma progression via metabolic regulation and ferroptosis insensitivity, offering a potential therapeutic target for glioma treatment.

Paired immunoglobin-like type 2 receptor beta (PILRB) mainly plays a crucial role in regulating innate immunity, but whether PILRB is involved in cancer is poorly understood. Here, we report that PILRB potentiates the PI3K/AKT pathway to drive gastric tumorigenesis by binding and stabilizing IRS4, which could hyperactivate the PI3K/AKT pathway. Firstly, the levels of PILRB are upregulated in human gastric cancer (GC) specimens and associated with poor prognosis in patients with GC. In addition, our data show that PILRB promotes cell proliferation, colony formation, cell migration and invasion in GC cells in vitro and in vivo. Mechanistically, PILRB recruits the deubiquitination enzymes OTUB1 to IRS4 and relieves K48-linked ubiquitination of IRS4, protecting IRS4 protein from proteasomal-mediated degradation and subsequent activation of the PI3K/AKT pathway. Importantly, the levels of PILRB are positively correlated with IRS4 in GC specimens. Meanwhile, we also found that PILRB reprogrammed cholesterol metabolism by altering ABCA1 and SCARB1 expression levels, and PILRB-expression confers GC cell resistance to statin treatment. Taken together, our findings illustrate that the oncogenic role of PILRB in gastric tumorigenesis, providing new insights into the regulation of PI3K/AKT signaling in GC and establishing PILRB as a biomarker for simvastatin therapy resistance in GC.

Lung adenocarcinoma (LUAD) is the main cause of cancer-related death worldwide. Understanding the mechanisms of LUAD progression may provide insights into targeted therapy approaches for this malignancy. Ubiquitin-conjugating enzyme 2 N (UBE2N) has been demonstrated to play key roles in the progression of various cancers. However, the functions and mechanisms underlying UBE2N expression in LUAD are still unclear. In this study, we found that UBE2N is highly expressed in LUAD and patients with high UBE2N expression in their tumors have poor clinical outcomes. Moreover, we showed that UBE2N interference significantly inhibited LUAD progression in vitro and in vivo. At the molecular level, we demonstrated that the UBE2N is a bona fide target of transcription factor SP1. SP1 directly bound to the promoter of UBE2N and upregulated its expression in LUAD cells, which in turn contributed to the progression of LUAD. Furthermore, we found that there is a strong positive correlation between the expression of SP1 and UBE2N in LUAD samples. Importantly, LUAD patients with concomitantly high expression of SP1 and UBE2N were significantly associated with poor clinical outcomes. In conclusion, our study demonstrated that the SP1-UBE2N signaling axis might play a key role in the malignant progression of LUAD, which provides new targets and strategies for the treatment of LUAD.

Triple-negative breast cancer (TNBC) is a highly malignant breast cancer subtype with a poor prognosis. Improved insight into the molecular biology basis of TNBC progression is urgently needed. Herein, we reported that POLD2 was highly expressed in TNBC and patients with high POLD2 expression in their tumors had poor clinical outcomes. In functional studies, knockdown of POLD2 inhibited the proliferation of TNBC. Mechanistically, we revealed that transcription factor E2F1 directly bound to the promoter of POLD2 and regulated its expression in TNBC cells, which in turn contributed to the proliferation of TNBC. Additionally, rescue experiments validated that E2F1-mediated cell proliferation in TNBC was dependent on POLD2. Taken together, our results elucidated a novel mechanism of the E2F1-POLD2 axis in TNBC proliferation, and POLD2 may be a potential therapeutic target for TNBC treatment.