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ER-Localized Deadenylase PNLDC1 Suppresses Colorectal Cancer Progression by Targeting the mRNA decay of TUBB4B


ABSTRACT: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, highlighting the urgent need for novel therapeutic strategies. In this study, we find that PNLDC1, an endoplasmic reticulum (ER)-localized deadenylase, lower expresses in 91 clinical CRC tissues. Using both in vitro and in vivo models, we identify PNLDC1 as a key tumor suppressor by modulating cell cycle progression in CRC. RNA-immunoprecipitation and sequencing analyses reveal that PNLDC1 binds cell cycle-associated mRNAs, with TUBB4B emerging as a critical target. PNLDC1 downregulates TUBB4B mRNA, whose regulated degradation is essential for PNLDC1’s tumor-suppressive function. Restoration of TUBB4B expression counteracts PNLDC1-mediated suppression of CRC cell proliferation, underscoring its pivotal role in CRC pathogenesis. Importantly, we demonstrate that the TUBB4B inhibitor, mebendazole, effectively suppresses the enhanced proliferation in lower-expression PNLDC1 models, including cell, mouse xenografts, and patient-derived tumor-like cell clusters, positioning it as a promising therapeutic agent. These findings establish PNLDC1 as a valuable biomarker and therapeutic target, paving the way for developing novel CRC treatments.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287213 | GEO | 2025/01/20

REPOSITORIES: GEO

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