Molecular and Cellular Oncology最新文献

Ferroptosis is a cell death mechanism triggered by lipid peroxidation. Our recent study linked cyst(e)ine availability with glutathione peroxidase 4 (GPX4) protein synthesis and ferroptosis mitigation via a Rag-mechanistic target of rapamycin complex 1 (mTORC1) axis, and proposed that co-targeting mTORC1 and ferroptosis is a promising strategy for cancer therapy.

The function of histone deacetylase 2 (HDAC2) in transcriptional regulation and its role in oncogenesis have been well established. Here we discuss a transcription-independent HDAC2 pathway controlling cancer-related protein stability via the mouse double minute 2 homolog (MDM2) ubiquitin ligase. In synovial sarcoma, HDAC2 inactivation demonstrates significant therapeutic effect by degradation of the SS18-SSX driver oncoprotein.

Aneuploidy, a common feature of cancer cells, results in increased sensitivity to the inhibition of the spindle assembly checkpoint (SAC) and the mitotic motor protein Kinesin Family Member 18A (KIF18A). We discuss the importance of drugs targeting SAC core members and KIF18A. We stress the need to assess the sensitivity to this class of drugs at appropriate time points, and propose that aneuploidy could serve as a biomarker to stratify patients for SAC-targeting treatments.

For recognition of specific regulatory sequences in the genome (i.e., response elements, REs), the tumor suppressor protein 53 kDa (p53) exhibits dose-dependent selectivity. In general, binding to REs linked to target genes involved in the positive regulation of cell death requires higher levels of p53 than those connected to cell survival. Our recent findings provide a mechanistic explanation for this phenomenon. Specifically, we demonstrate that subtle differences in DNA shape, encoded in RE DNA sequence, determine the utilization of two biochemically distinct DNA-binding modes, ultimately connected to different biological outcomes.

Conflicts between transcription and replication are a major source of replication stress. Our recent findings show that proper dephosphorylation of Serine 5 in the carboxy-terminal domain (CTD) of DNA-directed RNA polymerase II subunit RPB1 is needed to prevent such conflicts in human cells.

In a recent report, we have revealed a new interaction between the BRCA2 DNA repair associated protein (BRCA2) and the DEAD-box helicase 5 (DDX5) at DNA breaks that promotes unwinding DNA-RNA hybrids within transcribed chromatin and favors repair. Interestingly, BRCA2-DDX5 interaction is impaired in cells expressing the BRCA2^{T2 07A} missense variant found in breast cancer patients.

Identifying critical drivers of oncogenesis and tumor progression is essential for developing effective hepatocellular carcinoma (HCC) therapeutics. Our recent findings has demonstrated that targeting Ephrin Receptor A2 (EPHA2) suppresses HCC initiation and progression by dual inhibition of the Protein Kinase B (AKT) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling.

The metabolic checkpoint of ferroptosis remains obscure. We find that glucose favors system xc^- inhibitor-induced ferroptosis by activating pyruvate oxidation, thereby promoting fatty acid synthesis and subsequent lipid peroxidation. In contrast, the upregulation of pyruvate dehydrogenase kinase 4 (PDK4) switches into a ferroptosis-resistant state in pancreatic cancer cells.

Autophagy is a cellular self-degradative pathway. Our study unveiled a novel mechanism mediated by OFD1, the protein mutated in Oral-Facial-Digital type I syndrome, based on selective degradation of autophagic proteins, which enables cells to calibrate their self-degradation. We demonstrated that unrestrained autophagy contributes to renal cysts observed in Ofd1 mutants.

Release of nucleophosmin (NPM) from nucleoli following stress promotes rapid stabilization of the tumor suppressor p53 (TP53, best known as p53). Nucleoplasmic NPM binds to the ubiquitin ligase mouse double minute 2 (MDM2) and prevents MDM2-dependent p53 degradation. We recently demonstrated that sirtuin 7 (SIRT7) activates this pathway by directly deacetylating NPM following ultraviolet irradiation, indicating tumor-suppressive functions of SIRT7.