Cytosolic pH regulates proliferation and tumour growth by promoting expression of cyclin D1
A recent “Nature Metabolism” paper by the Dechant group (IBC) in collaboration with the Curioni (USZ), Opitz (USZ) and Peter (IBC) groups implicates increased cytosolic pH as a driver for cell proliferation by transcriptional activation of cyclin D1.
Stimulation of cell growth and proliferation goes hand in hand with changes in cellular metabolism, which is necessary for biomass production, but may itself signal to the cell cycle machinery to trigger proliferation, for example upon increased nutrient supply. These changes are also known as the Warburg effect and include enhanced glycolysis and elevated cytosolic pH (pHc). However, how high pHc regulates proliferation has long been unclear.
Koch et al. now provide a first molecular explanation by demonstrating that elevated pHc, mediated by the Na+/H+ exchanger NHE1, orchestrates a transcriptional program to drive cyclin D1 expression and G1 progression. Biochemical characterization revealed that the interaction of a transcription factor with a histone acetyl transferase acts as a pH-sensor capable of integrating different mitotic signals to regulate gene expression.
Moreover, they show that elevated pHc contributes to increased cyclin D1 expression in Malignant Pleural Mesotheliomas (MPM). Analysis of MPM tumors revealed that high NHE1 expression correlates with poor patient survival. Consistently, pharmacological reduction of pHc using an NHE1 inhibitor, decreases cyclin D1 levels and growth rates in MPM cell lines.
This suggests that an elevated pHc may generally help to evade growth suppression by stimulating G1 progression and provides a mechanism linking high pHc to oncogenic activation of cyclin D1, which could be exploited for therapeutic intervention or serve as a prognostic tool.
Link to the paper in "external pageNature Metabolism".