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 PARN‐like Domain Containing protein‐1 (PNLDC1), an endoplasmic reticulum‐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.