Pillar, N. | Search bioRxiv

bioRxiv2022

2-hydroxyglutarate controls centromere and heterochromatin conformation and function in the male germline

2-hydroxyglutarate (2HG) is recognized as an epigenetic regulator in cancer and some transient biological processes. Of all organs, the testis harbors the highest baseline physiological levels of 2HG, yet its putative functions in germ cell biology are unknown. Here we show that 2HG is generated in specific stages of spermatogenesis by the testis specific lactate dehydrogenase C (LDHC), beginning at the last stages of prophase I. Unexpectedly LDHC enters nuclei and concentrates in centromeres. LDHC-generated L-2HG controls centromere condensation and pericentromeric heterochromatin organization through multiple effects including clustering of chromocenters, centromere and chromocenter condensation and expression of satellite RNAs. These effects are rapid and specific to L but not D-2HG. In vivo depletion of L-2HG causes centromere malfunction and activation of the spindle assembly checkpoint. Our findings reveal that 2HG can directly affect centromere and pericentromeric heterochromatin conformation and function and is necessary for licensing chromosome segregation.

cell biology↗

bioRxiv2021

Dihydropyrimidinase-like 2 (DPYSL2) regulates breast cancer migration via a JAK/STAT3/vimentin axis

The intricate neuronal wiring during development requires cytoskeletal reorganization orchestrated by signaling cues. Considering that cytoskeletal remodeling is a hallmark of cell migration, we inquired whether metastatic cancer cells exploit the axon guidance proteins to migrate. Indeed, in breast cancer patients, we found a significant correlation between the mesenchymal markers and the expression of dihydropyrimidinase-like 2 (DPYSL2), a regulator of cytoskeletal dynamics in growing axons. Strikingly, DPYSL2 knockout in mesenchymal-like cells profoundly inhibited cell migration, invasion, stemness features, tumor growth rate, and metastasis. Next, we aimed to decode the molecular mechanism underlying this phenomenon and revealed an interaction between DPYSL2 and Janus kinase 1 (JAK1). This binding is crucial for triggering signal transducer and activator of transcription 3 (STAT3) and subsequently expressing vimentin, the pro-migratory intermediate filament. Collectively, we identified DPYSL2 as a molecular link between oncogenic signaling pathways and cytoskeletal reorganization in migrating breast cancer cells. Statement of significanceThis study shows that the axon guidance adaptor protein DPYSL2 is essential for promoting breast cancer migration. Specifically, this protein interacts with JAK1 to govern STAT3 signaling and subsequently vimentin expression.

cancer biology↗