AKAP8 promotes ovarian cancer progression and antagonizes PARP inhibitor sensitivity through regulating hnRNPUL1 transcription.

Ovarian cancer (OC) is the highest worldwide cancer mortality cause among gynecologic tumors, but its underlying molecular mechanism remains largely unknown. Here, we report that the RNA binding protein A-kinase anchoring protein 8 (AKAP8) is highly expressed in ovarian cancer and predicts poor prognosis for ovarian cancer patients. AKAP8 promotes ovarian cancer progression through regulating cell proliferation and metastasis. Mechanically, AKAP8 is enriched at chromatin and regulates the transcription of the specific hnRNPUL1 isoform. Moreover, AKAP8 phase separation modulates the hnRNPUL1 short isoform transcription. Ectopic expression of the hnRNPUL1 short isoform could partially rescue the growth inhibition effect of AKAP8-knockdown in ovarian cancer cells. In addition, AKAP8 modulates PARP1 expression through hnRNPUL1, and AKAP8 inhibition enhances PAPR inhibitor cytotoxicity in ovarian cancer. Together, our study uncovers the crucial function of AKAP8 condensation-mediated transcription regulation, and targeting AKAP8 could be potential for improvement of ovarian cancer therapy.

RNA m5C modification upregulates E2F1 expression in a manner dependent on YBX1 phase separation and promotes tumor progression in ovarian cancer.

5-Methylcytosine (m5C) is a common RNA modification that modulates gene expression at the posttranscriptional level, but the crosstalk between m5C RNA modification and biomolecule condensation, as well as transcription factor-mediated transcriptional regulation, in ovarian cancer, is poorly understood. In this study, we revealed that the RNA methyltransferase NSUN2 facilitates mRNA m5C modification and forms a positive feedback regulatory loop with the transcription factor E2F1 in ovarian cancer. Specifically, NSUN2 promotes m5C modification of E2F1 mRNA and increases its stability, and E2F1 binds to the NSUN2 promoter, subsequently reciprocally activating NSUN2 transcription. The RNA binding protein YBX1 functions as the m5C reader and is involved in NSUN2-mediated E2F1 regulation. m5C modification promotes YBX1 phase separation, which upregulates E2F1 expression. In ovarian cancer, NSUN2 and YBX1 are amplified and upregulated, and higher expression of NSUN2 and YBX1 predicts a worse prognosis for ovarian cancer patients. Moreover, E2F1 transcriptionally regulates the expression of the oncogenes MYBL2 and RAD54L, driving ovarian cancer progression. Thus, our study delineates a NSUN2-E2F1-NSUN2 loop regulated by m5C modification in a manner dependent on YBX1 phase separation, and this previously unidentified pathway could be a promising target for ovarian cancer treatment.

NAT10-mediated RNA acetylation enhances HNRNPUL1 mRNA stability to contribute cervical cancer progression.

N4-acetylcytidine (ac4C) is a lately discovered nucleotide modification that has been shown to be closely implicated in cancer. N-acetyltransferase10(NAT10) acts as an enzyme that regulates mRNA acetylation modifications. Currently, the role of NAT10-mediated RNA acetylation modification in cervical cancer remains to be elucidated. On the basis of transcriptome analysis of TCGA and GEO open datasets (GSE52904, GSE29570, GSE122697), NAT10 is upregulated in cervical cancer tissues and correlated with poor prognosis. Knockdown of NAT10 suppressed the cell proliferation, invasion, and migration of cervical cancer cells. The in vivo oncogenic function of NAT10 was also confirmed in xenograft models. Combined RNA-seq and acRIP-seq analysis revealed HNRNPUL1 as the target of NAT10 in cervical cancer. NAT10 positively regulate HNRNPUL1 expression by promoting ac4C modification and stability of HNRNPUL1 mRNA. Furthermore, depletion of HNRNPUL1 suppressed the cell division, invasion, and migration of cervical cancer. HNRNPUL1 overexpression partially restored cellular function in cervical cancer cells with NAT10 knockdown. Thus, this study demonstrates that NAT10 contributes to cervical cancer progression by enhancing HNRNPUL1 mRNA stability via ac4C modification, and NAT10-ac4C-HNRNPUL1 axis might be a potential target for cervical cancer therapy.

Stem Cell Therapy for Diabetic Foot Ulcers: Theory and Practice.

Diabetic foot ulcers are associated with increases in limb amputation, morbidity, and mortality. Recently, a stem cell application is emerging as promising adjuvant therapy. We presented available remedies by conducting a literature review on the application, safety, and efficacy of stem cell therapy. Relevant literature, including randomized control trials and article journals, was obtained from reputable search engines (PubMed, Scopus, and Web of Science). We analyzed five credible cohorts, with variable sources of stem cells, in a total of 216 participants, 151 males and 65 females, age (mean ± SD) of 64.5 ± 9.6 years. With an average success of 86.41% in all Wagner-II lesions, mesenchymal SCA (stem cell application) is safe and effective, hence can significantly prevent limb amputation.

KLF15 suppresses tumor growth and metastasis in Triple-Negative Breast Cancer by downregulating CCL2 and CCL7.

Kruppel like factor 15 (KLF15), a transcriptional factor belonging to the Kruppel-like factor (KLF) family of genes, has recently been reported as a tumor suppressor gene in breast cancer. However, the specific mechanisms by which KLF15 inhibits BrCa have not been elucidated. Here we investigated the role and mechanism of KLF15 in triple-negative breast cancer (TNBC). KLF15 expression and methylation were detected by RT-qPCR, RT-PCR and methylation-specific PCR in breast cancer cell lines and tissues. The effects of KLF15 on TNBC cell functions were examined via various cellular function assays. The specific anti-tumor mechanisms of KLF15 were further investigated by RNA sequence, RT-qPCR, Western blotting, luciferase assay, ChIP, and bioinformatics analysis. As the results showed that KLF15 is significantly downregulated in breast cancer cell lines and tissues, which promoter methylation of KLF15 partially contributes to. Exogenous expression of KLF15 induced apoptosis and G2/M phase cell cycle arrest, suppressed cell proliferation, metastasis and in vivo tumorigenesis of TNBC cells. Mechanism studies revealed that KLF15 targeted and downregulated C-C motif chemokine ligand 2 (CCL2) and CCL7. Moreover, transcriptome and metabolome analysis revealed that KLF15 is involved in key anti-tumor regulatory and metabolic pathways in TNBC. In conclusion, KLF15 suppresses cell growth and metastasis in TNBC by downregulating CCL2 and CCL7. KLF15 may be a prognostic biomarker in TNBC.

Interplay Between m6A RNA Methylation and Regulation of Metabolism in Cancer.

Methylation of adenosine in RNA to N6-methyladenosine (m6A) is widespread in eukaryotic cells with his integral RNA regulation. This dynamic process is regulated by methylases (editors/writers), demethylases (remover/erasers), and proteins that recognize methylation (effectors/readers). It is now evident that m6A is involved in the proliferation and metastasis of cancer cells, for instance, altering cancer cell metabolism. Thus, determining how m6A dysregulates metabolic pathways could provide potential targets for cancer therapy or early diagnosis. This review focuses on the link between the m6A modification and the reprogramming of metabolism in cancer. We hypothesize that m6A modification could dysregulate the expression of glucose, lipid, amino acid metabolism, and other metabolites or building blocks of cells by adaptation to the hypoxic tumor microenvironment, an increase in glycolysis, mitochondrial dysfunction, and abnormal expression of metabolic enzymes, metabolic receptors, transcription factors as well as oncogenic signaling pathways in both hematological malignancies and solid tumors. These metabolism abnormalities caused by m6A's modification may affect the metabolic reprogramming of cancer cells and then increase cell proliferation, tumor initiation, and metastasis. We conclude that focusing on m6A could provide new directions in searching for novel therapeutic and diagnostic targets for the early detection and treatment of many cancers.