Cytosolic pH regulates proliferation and tumour growth by promoting expression of cyclin D1

Our plain-English summary of Cytosolic pH regulates proliferation and tumour growth by promoting expression of cyclin D1, by L.M. Koch, E.S. Birkeland, S. Battaglioni, et al (Nature Metabolism, 2020).

The study

• Authors: L.M. Koch, E.S. Birkeland, S. Battaglioni, X. Helle, M. Meerang, S. Hiltbrunner, A.J. Ibáñez, M. Peter, A. Curioni-Fontecedro, I. Opitz, R. Dechant
• Journal: Nature Metabolism
• Published: 2020;2(11):1212-1222
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Enhanced growth and proliferation of cancer cells are accompanied by profound changes in cellular metabolism. These metabolic changes are also common under physiological conditions, and include increased glucose fermentation accompanied by elevated cytosolic pH (pHc)1,2. However, how these changes contribute to enhanced cell growth and proliferation is unclear. Here, we show that elevated pHc specifically orchestrates an E2F-dependent transcriptional programme to drive cell proliferation by promoting cyclin D1 expression. pHc-dependent transcription of cyclin D1 requires the transcription factors CREB1, ATF1 and ETS1, and the histone acetyltransferases p300 and CBP. Biochemical characterization revealed that the CREB1-p300/CBP interaction acts as a pH sensor and coincidence detector, integrating different mitotic signals to regulate cyclin D1 transcription. We also show that elevated pHc contributes to increased cyclin D1 expression in malignant pleural mesotheliomas (MPMs), and renders these cells hypersensitive to pharmacological reduction of pHc. Taken together, these data demonstrate that elevated pHc is a critical cellular signal regulating G1 progression, and provide a mechanism linking elevated pHc to oncogenic activation of cyclin D1 in MPMs, and possibly other cyclin D1~dependent tumours. Thus, an increase of pHc may represent a functionally important, early event in the aetiology of cancer that is amenable to therapeutic intervention.

In plain English

This was a laboratory study of how the acidity inside cells (cytosolic pH) affects cell division. It did not study asbestos exposure. Working mainly with cultured human RPE-1 cells, the authors lowered cytosolic pH with the drug dimethyl amiloride (DMA) or by silencing the sodium–hydrogen exchanger NHE1. This stopped cells early in the division cycle and reduced cyclin D1, a protein that drives cell division. Further experiments pointed to the binding between the proteins CREB1 and p300/CBP acting as a pH sensor. Cell lines from malignant pleural mesothelioma (MPM) had high cyclin D1 compared with a control line from a healthy donor, and lines with higher cytosolic pH were more sensitive to DMA. Tumour samples from 96 MPM patients at University Hospital Zurich were also examined. Patients with high NHE1 (45 patients) had significantly higher cyclin D1 than those with low NHE1 (51 patients), and high NHE1 was linked to poorer survival (hazard ratio 1.679, confidence interval 1.102 to 2.558). The authors concluded that raised cytosolic pH promotes cyclin D1 expression and may represent an early step in cancer development that drugs could target.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory experiments on cultured human cells, combined with retrospective immunohistochemical analysis of resected MPM tumour specimens and analysis of public databases (CCLE, TCGA)
• Who was studied: Mainly hTERT-immortalized RPE-1 cells, plus primary fibroblasts, PDAC cell lines and MPM cell lines (Meso-1, Mero-82, H28) compared with a control cell line (MeT-5A) from a healthy donor. Also tumour specimens from 96 MPM patients (9 female, 87 male; 70 epithelioid, 16 biphasic, 5 sarcomatoid, 5 undefined) from a previously described University Hospital Zurich cohort, and the TCGA-MESO cohort.
• Exposure: No asbestos exposure was studied. The experimental factor was cytosolic pH, lowered by inhibiting sodium–hydrogen exchangers with dimethyl amiloride (DMA) or by RNA interference against NHE1.
• Main results:
  • In cultured cells, DMA treatment or RNA interference against NHE1 caused cells to stop in the G1 phase of the cell cycle.
  • DMA treatment delayed the build-up of cyclin D1 protein in cells.
  • The authors concluded that the interaction between phosphorylated CREB1 and p300/CBP acts as a pH sensor.
  • MPM cell lines had high levels of nuclear cyclin D1 compared with a control cell line from a healthy donor. MPM cell lines with higher cytosolic pH were significantly more sensitive to DMA.
  • In tumour samples from the 96 MPM patients, cyclin D1 expression was significantly higher in patients with high NHE1 expression (45 patients) than in those with low NHE1 expression (51 patients).
  • In the same MPM patient cohort, high NHE1 expression was associated with poorer survival: hazard ratio 1.679 (confidence interval 1.102 to 2.558).
  • In the TCGA mesothelioma cohort (49 patients with high and 37 with low NHE1 expression), the hazard ratio was 1.95 (confidence interval 1.16 to 3.30).
• The authors' conclusion: The authors concluded that elevated cytosolic pH drives a transcriptional programme for cell-cycle progression through cyclin D1. They proposed that this may represent an early step in cellular transformation that could be targeted by drugs, and that it contributes to increased cyclin D1 in MPMs.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma.

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