Abstract 4746: Downregulation of PDLIM2 promotes tumor growth through regulation of oncometabolites and HIF-1α pathway

Abstract Cancer is increasingly recognized as a disease driven by dysregulated cellular metabolism, and elucidating the molecular mechanisms behind these metabolic alterations is essential for developing effective targeted therapies. In present study, we investigated the pro-tumorigenic role of PDLIM2 (PDZ and LIM domain 2) downregulation in lung cancer progression, with a particular focus on its impact on mitochondrial metabolism and hypoxia-inducible factor-1α (HIF-1α) signaling. Our analysis revealed that PDLIM2 expression is significantly downregulated in lung cancer tissues, and this reduction correlates with unfavorable patient prognosis. Transcriptomic profiling indicated that PDLIM2 regulates a network of genes associated with mitochondrial function. Mechanistically, PDLIM2 downregulation impaired the expression of tricarboxylic acid (TCA) cycle genes, notably those encoding succinate dehydrogenase (SDH) subunits. This disruption led to mitochondrial dysfunction, accumulation of succinate and other oncometabolites. These metabolic disturbances contributed to the stabilization and activation of HIF-1α, a transcription factor known to drive tumor progression under hypoxic conditions. Further studies indicated that HIF-1α expression is elevated across all stages of lung cancer, and its levels are inversely correlated with PDLIM2 expression in patient samples. To further validate this axis, we performed an in vivo study with cancer animal model using PX-478, an orally bioavailable HIF-1α inhibitor. Treatment with PX-478 significantly attenuated the tumor growth promoted by PDLIM2 knockdown, supporting the functional relevance of HIF-1α activation in mediating the oncogenic consequences of PDLIM2 loss. Collectively, these findings highlight a novel regulatory link between PDLIM2, mitochondrial metabolism, and HIF-1α signaling in lung cancer. They emphasize the tumor-promoting effects of PDLIM2 downregulation and suggest that therapeutic inhibition of HIF-1α may represent a promising precision strategy for patients with PDLIM2-deficient tumors. Citation Format: Tsung-Hsien Chuang, Jing-Xing Yang, Yu-Chen Chuang, Jen-Chih Tseng, Yi-Ling Liu, Chao-Yang Lai. Downregulation of PDLIM2 promotes tumor growth through regulation of oncometabolites and HIF-1α pathway abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4746.