HMGA2 drives the IGFBP1/AKT pathway to counteract the increase in P27KIP1 protein levels in mtDNA/RNA‐less cancer cells

Recent comprehensive analyses of mtDNA and orthogonal RNA‐sequencing data revealed that in numerous human cancers, mtDNA copy numbers and mtRNA amounts are significantly reduced, followed by low respiratory gene expression. Under such conditions (called mt‐Low), cells encounter severe cell proliferation defects; therefore, they must acquire countermeasures against this fatal disadvantage during malignant transformation. This study elucidated a countermeasure against the mt‐Low condition‐induced antiproliferative effects in hepatocellular carcinoma (HCC) cells. The mechanism relied on the architectural transcriptional regulator HMGA2, which was preferably expressed in HCC cells of the mt‐Low type in vitro and in vivo. Detailed in vitro analyses suggest that HMGA2 regulates insulin‐like growth factor binding protein 1 (IGFBP1) expression, leading to AKT activation, which then phosphorylates the cyclin‐dependent kinase inhibitor (CKI), P27KIP1, and facilitates its ubiquitin‐mediated degradation. Accordingly, intervention in the HMGA2 function by RNAi resulted in an increase in P27KIP1 levels and an induction of senescence‐like cell proliferation inhibition in mt‐Low‐type HCC cells. Conclusively, the HMGA2/IGFBP1/AKT axis has emerged as a countermeasure against P27KIP1 CKI upregulation under mt‐Low conditions, thereby circumventing cell proliferation inhibition and supporting the tumorigenic state. Notably, similar to in vitro cell lines, HMGA2 was likely to regulate IGFBP1 expression in HCC in vivo, thereby contributing to poor patient prognosis. Considering the significant number of cases under mt‐Low or the threat of CKI upregulation cancer‐wide, the axis is noteworthy as a vulnerability of cancer cells or target for tumor‐agnostic therapy inducing irreversible cell proliferation inhibition via CKI upregulation in a large population with cancer. mtDNA copy numbers and mtRNA amounts are reduced, followed by low respiratory gene expression in numerous cancer cells. High expression of HMGA2 activates the IGFBP1/AKT pathway, circumventing mitochondria deficiency‐caused cell proliferation defects. Intervention in the HMGA2 function results in an increase in P27KIP protein levels and an induction of senescence‐like cell cycle arrest in cancer cells.