Molecular and Cellular Oncology最新文献

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.

The PIDDosome is a Caspase-2-activating platform assembling in response to centrosome amplification or genotoxic stress. We have recently shown that both stimuli depend on ANKRD26 (ankyrin repeat domain-containing protein 26)-mediated localization of PIDD1 (p53-inducible protein with death domain) at the centrosome, demonstrating how this organelle can directly influence cell fate.

The rate-limiting enzyme of serine biosynthesis, 3-phosphoglycerate dehydrogenase (PHGDH), contributes to rapid growth and proliferation when it is overexpressed in cancer. We recently described the metabolic adaptations that occur upon PHGDH inhibition in osteosarcoma. PHGDH inhibition causes metabolite accumulation that activates the mechanistic target of rapamycin (mTOR) signaling, sensitizing osteosarcoma to non-rapalog mTOR inhibition.

The glycolytic enzyme PGAM1 is overexpressed in gliomas where it efficiently facilitates the repair of DNA damage. Mechanistically, PGAM1 prevents inactivation of the ataxia-telangiectasia mutated (ATM) signaling pathway by sequestering the wild-type p53-induced phosphatase 1 (WIP1) in the cytoplasm. Genetic inhibition of PGAM1 expression subsequently sensitizes glioma cells against irradiation and chemotherapy-induced DNA damage.

The mutants of the tumor suppressor protein p53 form protein aggregates. It has been proposed that these aggregates propagate like prions, albeit the detailed mechanism of the propagation is unclear. Our recent study revealed that sulfated glycosaminoglycans, especially highly sulfated domains of heparan sulfate (heparan sulfate S-domains), participate in cancer pathology by mediating transcellular propagation of p53 aggregates.

Selective autophagy contributes to the degradation of condensates, such as sequestosome 1-bodies, also called p62/SQSTM1-bodies. We showed that endogenous p62 forms gel-like structures, which serve as platforms for autophagosome formation and nuclear factor erythroid 2-related factor 2 (NRF2) activation. Further, p62-mediated NRF2 activation is not cytotoxic, but combination of NRF2 activation with impaired bulk and selective autophagy causes liver injury.