TIPE drives a cancer stem-like phenotype by promoting glycolysis via PKM2/HIF-1α axis in melanoma

  1. Maojin Tian
  2. Le Yang
  3. Ziqian Zhao
  4. Jigang Li
  5. Lianqing Wang
  6. Qingqing Yin
  7. Wei Hu
  8. Yunwei Lou
  9. Jianxin Du
  10. Peiqing Zhao

  • Curated by eLife

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    This important study investigates the molecular mechanisms underpinning how the tumor necrosis factor alpha-induced protein, TIPE, regulates aerobic glycolysis to promote tumor growth in melanoma. Data using multiple independent approaches provide new insights into the molecular mechanisms underpinning aerobic glycolysis, also known as the Warburg Effect, in melanoma cells. The claims of the authors are solid, although more in-depth metabolic assays as well as the inclusion of melanoma patient survival analysis in TIPE high and low tumors would strengthen the study. The work will be of interest to biomedical researchers working in cancer and metabolism.

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Abstract

TIPE (TNFAIP8) has been identified as an oncogene and participates in tumor biology. However, how its role in the metabolism of tumor cells during melanoma development remains unclear. Here, we demonstrated that TIPE promoted glycolysis by interacting with pyruvate kinase M2 (PKM2) in melanoma. We found that TIPE induced PKM2 dimerization, thereby facilitating its translocation from the cytoplasm to the nucleus. TIPE-mediated PKM2 dimerization consequently promoted HIF-1α activation and glycolysis, which contributed to melanoma progression and increased its stemness features. Notably, TIPE specifically phosphorylated PKM2 at Ser 37 in an ERK-dependent manner. Consistently, the expression of TIPE was positively correlated with the levels of PKM2 Ser37 phosphorylation and cancer stem cell markers in melanoma tissues from clinical samples and tumor bearing mice. In summary, our findings indicate that the TIPE/PKM2/HIF-1α signaling pathway plays a pivotal role in promoting cancer stem cell properties by facilitating the glycolysis, which would provide a promising therapeutic target for melanoma intervention.

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  1. Version published to 10.7554/elife.92741.1 on eLife
  2. Version published to 10.7554/elife.92741 on eLife
  3. eLife

    eLife assessment

    This important study investigates the molecular mechanisms underpinning how the tumor necrosis factor alpha-induced protein, TIPE, regulates aerobic glycolysis to promote tumor growth in melanoma. Data using multiple independent approaches provide new insights into the molecular mechanisms underpinning aerobic glycolysis, also known as the Warburg Effect, in melanoma cells. The claims of the authors are solid, although more in-depth metabolic assays as well as the inclusion of melanoma patient survival analysis in TIPE high and low tumors would strengthen the study. The work will be of interest to biomedical researchers working in cancer and metabolism.

  4. eLife

    Reviewer #1 (Public Review):

    Summary:
    Tian et al. describe how TIPE regulates melanoma progression, stemness, and glycolysis. The authors link high TIPE expression to increased melanoma cell proliferation and tumor growth. TIPE causes dimerization of PKM2, as well as translocation of PKM2 to the nucleus, thereby activating HIF-1alpha. TIPE promotes the phosphorylation of S37 on PKM2 in an ERK-dependent manner. TIPE is shown to increase stem-like phenotype markers. The expression of TIPE is positively correlated with the levels of PKM2 Ser37 phosphorylation in murine and clinical tissue samples. Taken together, the authors demonstrate how TIPE impacts melanoma progression, stemness, and glycolysis through dimeric PKM2 and HIF-1alpha crosstalk.

    Strengths:
    The authors manipulated TIPE expression using both shRNA and overexpression approaches throughout the manuscript. Using these models, they provide strong evidence of the involvement of TIPE in mediating PKM2 Ser37 phosphorylation and dimerization. The authors also used mutants of PKM2 at S37A to block its interaction with TIPE and HIF-1alpha. In addition, an ERK inhibitor (U0126) was used to block the phosphorylation of Ser37 on PKM2. The authors show how dimerization of PKM2 by TIPE causes nuclear import of PKM2 and activation of HIF-1alpha and target genes. Pyridoxine was used to induce PKM2 dimer formation, while TEPP-46 was used to suppress PKM2 dimer formation. TIPE maintains stem cell phenotypes by increasing the expression of stem-like markers. Furthermore, the relationship between TIPE and Ser37 PKM2 was demonstrated in murine and clinical tissue samples.

    Weaknesses:
    The evaluation of how TIPE causes metabolic reprogramming can be better assessed using isotope tracing experiments and improved bioenergetic analysis.

  5. eLife

    Reviewer #2 (Public Review):

    In this article, Tian et al present a convincing analysis of the molecular mechanisms underpinning TIPE-mediated regulation of glycolysis and tumor growth in melanoma. The authors begin by confirming TIPE expression in melanoma cell lines and identify "high" and "low" expressing models for functional analysis. They show that TIPE depletion slows tumour growth in vivo, and using both knockdown and over-expression approaches, show that this is associated with changes in glycolysis in vitro. Compelling data using multiple independent approaches is presented to support an interaction between TIPE and the glycolysis regulator PKM2, and the over-expression of TIPE-promoted nuclear translocation of PKM2 dimers. Mechanistically, the authors also demonstrate that PKM2 is required for TIPE-mediated activation of HIF1a transcriptional activity, as assessed using an HRE-promoter reporter assay, and that TIPE-mediated PKM2 dimerization is p-ERK dependent. Finally, the dependence of TIPE activity on PKM2 dimerization was demonstrated on tumor growth in vivo and in the regulation of glycolysis in vitro, and ectopic expression of HIF1a could rescue the inhibition of PKM2 dimerization in TIPE overexpressing cells and reduced induction of general cancer stem cell markers, showing a clear role for HIF1a in this pathway. The main conclusions of this paper are well supported by data, but some aspects of the experiments need clarification and some data panels are difficult to read and interpret as currently presented.

    The detailed mechanistic analysis of TIPE-mediated regulation of PKM2 to control aerobic glycolysis and tumor growth is a major strength of the study and provides new insights into the molecular mechanisms that underpin the Warburg effect in cancer cells. However, despite these strengths, some weaknesses were noted, which if addressed will further strengthen the study.

    1. The analysis of patient samples should be expanded to more directly measure the relationship between TIPE levels and melanoma patient outcome and progression (primary vs metastasis), to build on the association between TIPE levels and proliferation (Ki67) and hypoxia gene sets that are currently shown.

    2. The duration of the in vivo experiments was not clearly defined in the figures, however, it was clear from the tumor volume measurements that they ended well before standard ethical endpoints in some of the experiments. A rationale for this should be provided because longer-duration experiments might significantly change the interpretation of the data. For example, does TIPE depletion transiently reduce or lead to sustained reductions in tumor growth?

    3. The analysis of general cancer stem cell markers is solid and interesting, however inclusion of neural crest stem cell markers that are more relevant to melanoma biology would greatly strengthen this aspect of the study.

    4. The authors should take care that all data panels are clearly readable in the figures to facilitate appropriate interpretation by the reader.

  6. Version published to 10.1101/2023.11.14.567124v1 on bioRxiv