PRL‐3 induces a positive signaling circuit between glycolysis and activation of STAT1/2

Multiple myeloma (MM) is an incurable hematologic malignancy resulting from the clonal expansion of plasma cells. MM cells are interacting with components of the bone marrow microenvironment such as cytokines to survive and proliferate. Phosphatase of regenerating liver (PRL)‐3, a cytokine‐induced oncogenic phosphatase, is highly expressed in myeloma patients and is a mediator of metabolic reprogramming of cancer cells. To find novel pathways and genes regulated by PRL‐3, we characterized the global transcriptional response to PRL‐3 overexpression in two MM cell lines. We used pathway enrichment analysis to identify pathways regulated by PRL‐3. We further confirmed the hits from the enrichment analysis with in vitro experiments and investigated their function. We found that PRL‐3 induced expression of genes belonging to the type 1 interferon (IFN‐I) signaling pathway due to activation of signal transducer and activator of transcription (STAT) 1 and STAT2. This activation was independent of autocrine IFN‐I secretion. The increase in STAT1 and STAT2 did not result in any of the common consequences of increased IFN‐I or STAT1 signaling in cancer. Knockdown of STAT1/2 did not affect the viability of the cells, but decreased PRL‐3‐induced glycolysis. Interestingly, glucose metabolism contributed to the activation of STAT1 and STAT2 and expression of IFN‐I‐stimulated genes in PRL‐3‐overexpressing cells. In summary, we describe a novel signaling circuit where the key IFN‐I‐activated transcription factors STAT1 and STAT2 are important drivers of the increase in glycolysis induced by PRL‐3. Subsequently, increased glycolysis regulates the IFN‐I‐stimulated genes by augmenting the activation of STAT1/2.