Abstract 184: PHF6-LEO1 axis depletion drives aggressive colorectal cancer through WNT activation and metabolic reprogramming with therapeutic implications

Abstract Colorectal cancer (CRC) progression is closely linked to alterations in key signaling pathways and metabolic reprogramming. The WNT signaling pathway plays a critical role in regulating cell development and proliferation, and its abnormal activation is a hallmark of CRC. Plant Homeodomain 6 (PHF6), a chromatin-associated factor, is known for its roles in clonal hematopoiesis, ribosome biogenesis, DNA repair, and aging, and is frequently mutated in lymphoid cancers and leukemia. In this study, RNA-seq and ATAC-seq were conducted to investigate the function of PHF6, we identified PHF6 as a novel regulator of the WNT signaling pathway. We found that PHF6 depletion activate WNT signaling and proliferation of colon cancer cells. In the AOM/DSS model, PHF6 knockout mice exhibited larger polyp formation compared to wild type mice, with polyps extending into the proximal region. Proximal CRC is more prevalent and aggressive and has distinct genetic features compared to distal CRC. Alterations in proximal CRC include the PIK3CA mutation and CpG island methylator phenotype (CIMP)-high frequency, the development of CIMP is followed by global gene expression alteration and metabolic changes. However, the molecular mechanisms of this type of cancer are not fully understood. We observed a reduced levels of LEO1, the transcriptional elongation partner of PHF6 within the PAF1 complex, in the proximal region of PHF6 KO mice. We identified LEO1 and SETD1A as epigenetic regulators of lipid homeostasis in colon cancer cells and patient samples with matched normal. Dysregulation of lipid metabolism in cancer cells impacts tumor initiation, progression, and metastasis. LEO1 KO cells exhibited reduced expression and activation of SREBP1, a master regulator of lipid metabolism, under glucose starvation. These effects were further enhanced by SETD1A knockdown. LEO1 was found to localize to the nucleus and is required for the nuclear localization of SETD1A under nutrient stress. These cells showed an altered cell cycle, resulting in reduced proliferation but increased metastatic potential. These findings suggest that the PHF6-LEO1 axis plays a crucial role in the regional development and metastasis, underscoring its importance in advancing our understanding of tumor biology and guiding targeted therapy development. Citation Format: Su Chan Park, Shinae Park, Ji-Yeon Lee, Taehan Yoon, So Hyun Kwon, Jung-Shin Lee, Eun Jung Park, Ji Min Lee. PHF6-LEO1 axis depletion drives aggressive colorectal cancer through WNT activation and metabolic reprogramming with therapeutic implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 184.