Merkel Cell Polyomavirus Small T Antigen Promotes Pro-Glycolytic Metabolic Perturbations Required for Transformation

Abstract

Merkel cell polyomavirus (MCPyV) is an etiological agent of Merkel cell carcinoma (MCC), a highly aggressive skin cancer. The MCPyV small tumor antigen (ST) is required for maintenance of MCC and can transform normal cells. To gain insight into cellular perturbations induced by MCPyV ST, we performed transcriptome analysis of normal human fibroblasts with inducible expression of ST. MCPyV ST dynamically alters the cellular transcriptome with increased levels of glycolytic genes, including the monocarboxylate lactate transporter SLC16A1 (MCT1). Extracellular flux analysis revealed increased lactate export reflecting elevated aerobic glycolysis in ST expressing cells. Inhibition of MCT1 activity suppressed the growth of MCC cell lines and impaired MCPyV-dependent transformation of IMR90 cells. Both NF-κB and MYC have been shown to regulate MCT1 expression. While MYC was required for MCT1 induction, MCPyV-induced MCT1 levels decreased following knockdown of the NF-κB subunit RelA, supporting a synergistic activity between MCPyV and MYC in regulating MCT1 levels. Several MCC lines had high levels of MYCL and MYCN but not MYC. Increased levels of MYCL was more effective than MYC or MYCN in increasing extracellular acidification in MCC cells. Our results demonstrate the effects of MCPyV ST on the cellular transcriptome and reveal that transformation is dependent, at least in part, on elevated aerobic glycolysis.

Merkel cell carcinoma

“…Expression of ST can promote substantial changes in gene expression, including the induction of proglycolytic genes, and can induce aerobic glycolysis in fibroblasts 56 . Malignant, rapidly growing tumour cells typically have glycolytic rates up to 200-fold higher than those of their normal tissues of origin (a phenomenon known as the Warburg effect).…”

Merkel Cell Polyomavirus Small Tumor Antigen Activates Matrix Metallopeptidase-9 Gene Expression for Cell Migration and Invasion

“…Therefore, these results suggest that for MCV sT-related oncogenic functions in MCC, the basement membrane must be degraded in order for invasion of tumor cells into the circulatory system for metastasis to occur (37). Aligned with these observations, transcriptome analysis has suggested that certain markers associated with EMT are increased upon MCV-sT expression (38).…”

Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC

“…a sT can (i) preserve 4E-BP1 hyperphosphorylation resulting in dysregulated cap-dependent translation [31], (ii) through inhibition of SCF Fbx7 ubiquitin ligase stabilize their cellular targets and MCPyV LT [32], (iii) interact with NEMO thereby inhibiting NF-κB-mediated transcription [33–35], (iv) lead to a motile and migratory phenotype by promoting microtubule destabilization [36], (v) elevate aerobic glycolysis by regulating MCT-1 levels [37] and (vi) inactivate p53 pathway through recruitment of MAX and MYCL and binding to P400 complex resulting in increased expression of the p53 inhibitor MDM2. b In tumor cells, the C-terminal domains of LT containing several crucial elements required for viral replication are consistently truncated by tumor-associated mutations.…”

“…It was recently demonstrated that MCPyV sT specifically recruits l -myc-1 proto-oncogene protein (MYCL) and myc-associated factor X (MAX) to the 15-component p400 complex. sT, MYCL and the p400 complex bind specifically to transcription start sites and promote gene expression [37]. Wild-type sT, but not a p400 binding mutant, can cooperate with MYCL to transform human fibroblasts.…”