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Phospholipase D6 activates Wnt/β-catenin signaling through mitochondrial metabolic reprogramming to promote tumorigenesis in colorectal cancer
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Phospholipase D6 activates Wnt/β-catenin signaling through mitochondrial metabolic reprogramming to promote tumorigenesis in colorectal cancer
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Journal Article
Phospholipase D6 activates Wnt/β-catenin signaling through mitochondrial metabolic reprogramming to promote tumorigenesis in colorectal cancer
2025
Overview
Phospholipase D6 (PLD6) is a critical enzyme involved in mitochondrial fusion with a key role in spermatogenesis. However, the role of PLD6 in cancer remains unknown. Notably, Wnt signaling, energy metabolism and mitochondrial function show complex interactions in colorectal cancer (CRC) progression. Here we found that PLD6 is highly expressed in CRC and positively correlated with poor prognosis. We present a novel function of PLD6 in activating Wnt/β-catenin signaling by enhancing mitochondrial metabolism. PLD6 depletion suppresses the oncogenic properties of CRC cells and impairs mitochondrial respiration, leading to reduced mitochondrial length, membrane potential, calcium levels and reactive oxygen species. PLD6 depletion also disrupts mitochondrial metabolic reprogramming by inhibiting the tricarboxylic acid cycle and mitochondrial oxidative phosphorylation, resulting in altered intracellular levels of citrate and acetyl-CoA—both key modulators of Wnt/β-catenin activation. PLD6-mediated acetyl-CoA production enhances β-catenin stability by promoting its acetylation via the acetyltransferases CREB-binding protein and P300/CREB-binding-protein-associated factor. Consequently, PLD6 ablation reduces cancer stem cell-associated gene expression downstream of Wnt/β-catenin signaling, suppressing stem-like traits and chemoresistance to 5-fluorouracil. Furthermore, PLD6 depletion attenuates CRC tumorigenesis in both subcutaneous and orthotopic tumor models. Overall, PLD6 acts as an oncogenic switch by promoting mitochondria-mediated retrograde signaling, thereby regulating Wnt signaling in CRC.
PLD6 drives Wnt signaling and cancer progression in CRC
This study explores the role of a protein called phospholipase D6 (PLD6) in colorectal cancer (CRC). PLD6 is known to be involved in mitochondrial function, but its role in cancer was unclear. Researchers found that PLD6 is more active in CRC tissues compared with normal tissues, and higher levels of PLD6 are linked to worse outcomes for patients. Researchers used techniques such as CRISPR–Cas9 (a gene-editing tool) to modify PLD6 levels in cells and observed changes in cell behavior. They found that PLD6 promotes cancer cell growth, movement and survival by affecting mitochondrial metabolism and a signaling pathway called Wnt/β-catenin, which is important for cell growth and development. The study suggests that targeting PLD6 could be a potential strategy for treating CRC, as it may help reduce tumor growth and improve the effectiveness of chemotherapy.
This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group,생화학분자생물학회
Subject
/ Animals
/ Biomedical and Life Sciences
/ Cancer
/ Colorectal Neoplasms - genetics
/ Colorectal Neoplasms - metabolism
/ Colorectal Neoplasms - pathology
/ CRISPR
/ Cyclic AMP response element-binding protein
/ Enzymes
/ Gene Expression Regulation, Neoplastic
/ Humans
/ Male
/ Mice
/ Neoplastic Stem Cells - metabolism
/ Phospholipase D - metabolism
/ Proteins
/ 생화학
