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Background <p>Colorectal cancer (CRC) frequently exhibits hypoxic regions due to poor vascularization, leading to the stabilization of hypoxia-inducible factor 1 alpha (HIF-1α). Moreover, mutations in the tumour suppressor p53 occur in approximately half of all CRCs. While the individual roles of both transcription factors in tumour cell survival are well characterized, their interaction and its influence on the metabolic adaptation of CRC cells under hypoxic stress remain unclear.</p> Methods <p>Using HCT116 CRC cells with targeted deletions of TP53 and HIF1A, we examined the effects of p53 loss on HIF-1 signalling and the respective consequences for metabolic adaptation as well as the survival of CRC cells under moderate (1% O₂) and severe (0.1% O₂) hypoxia.</p> Results <p>Severe hypoxia stabilized p53 protein levels despite the transcriptional repression of <i>TP53</i>, possibly through posttranslational mechanisms and dependent on nutrient availability. In contrast to the assumption that p53 is transcriptionally inactive under hypoxia, we observed stable expression of p53 target genes (<i>P21</i>, <i>BAX</i>) under severe hypoxia, indicating functional transactivation. Loss of p53 impaired the early induction of HIF-1 target genes (<i>VEGF</i>, <i>PHD2</i>), although HIF-1α protein levels and DNA binding were unaffected, suggesting a coactivator role for p53. Furthermore, compared with wild-type cells, p53-deficient cells presented delayed but exaggerated expression of glycolytic genes, including <i>Glucose Uptake Transporter 1 (GLUT1)</i>,<i> Phosphofructokinase Liver-Type (PFKL) and Lactate Dehydrogenase A (LDHA)</i>, under hypoxia, with no impairment of glycolytic function or cell viability. Remarkably, even HIF1A knockout cells preserved glycolysis, whereas glycolytic genes were significantly downregulated, indicating HIF-1-independent metabolic compensation.</p> Conclusion <p>Our findings position p53 as a temporal gatekeeper and key regulator of hypoxic adaptation in CRC cells, coordinating early gene induction and metabolic responses. The ability of CRC cells to maintain glycolysis despite the loss of p53, respectively, HIF-1α underscores the existence of compensatory HIF-independent pathways. Targeting these alternative circuits may represent a promising strategy in hypoxic, p53-deficient CRC.</p>

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P53 – a new player in the metabolic adaptation of colorectal carcinoma cells under hypoxia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月19日

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  • Stefanie Saoub,
  • Eric Metzen,
  • Basant Kumar Thakur,
  • Yoshiyuki Henning,
  • Yves Schild,
  • Tristan Leu,
  • Joachim Fandrey,
  • Anna Wrobeln

摘要

Background

Colorectal cancer (CRC) frequently exhibits hypoxic regions due to poor vascularization, leading to the stabilization of hypoxia-inducible factor 1 alpha (HIF-1α). Moreover, mutations in the tumour suppressor p53 occur in approximately half of all CRCs. While the individual roles of both transcription factors in tumour cell survival are well characterized, their interaction and its influence on the metabolic adaptation of CRC cells under hypoxic stress remain unclear.

Methods

Using HCT116 CRC cells with targeted deletions of TP53 and HIF1A, we examined the effects of p53 loss on HIF-1 signalling and the respective consequences for metabolic adaptation as well as the survival of CRC cells under moderate (1% O₂) and severe (0.1% O₂) hypoxia.

Results

Severe hypoxia stabilized p53 protein levels despite the transcriptional repression of TP53, possibly through posttranslational mechanisms and dependent on nutrient availability. In contrast to the assumption that p53 is transcriptionally inactive under hypoxia, we observed stable expression of p53 target genes (P21, BAX) under severe hypoxia, indicating functional transactivation. Loss of p53 impaired the early induction of HIF-1 target genes (VEGF, PHD2), although HIF-1α protein levels and DNA binding were unaffected, suggesting a coactivator role for p53. Furthermore, compared with wild-type cells, p53-deficient cells presented delayed but exaggerated expression of glycolytic genes, including Glucose Uptake Transporter 1 (GLUT1), Phosphofructokinase Liver-Type (PFKL) and Lactate Dehydrogenase A (LDHA), under hypoxia, with no impairment of glycolytic function or cell viability. Remarkably, even HIF1A knockout cells preserved glycolysis, whereas glycolytic genes were significantly downregulated, indicating HIF-1-independent metabolic compensation.

Conclusion

Our findings position p53 as a temporal gatekeeper and key regulator of hypoxic adaptation in CRC cells, coordinating early gene induction and metabolic responses. The ability of CRC cells to maintain glycolysis despite the loss of p53, respectively, HIF-1α underscores the existence of compensatory HIF-independent pathways. Targeting these alternative circuits may represent a promising strategy in hypoxic, p53-deficient CRC.