Unveiling the ZNF384-INTS13-hnRNPC axis as a therapeutic vulnerability in cervical cancer

Abstract

Cervical cancer remains a major global health burden, necessitating the identification of novel therapeutic targets to overcome the limitations of current treatments. Here, we comprehensively investigated the role of integrator complex subunit 13 (INTS13) in cervical cancer progression. Our analysis of publicly available The Cancer Genome Atlas (TCGA) datasets revealed that INTS13 is significantly overexpressed in cervical cancer tissues across various histological subtypes, correlating with advanced tumor T-stage and predicting poorer overall survival. Single-cell RNA sequencing further localized INTS13 expression predominantly to malignant epithelial cells within the tumor microenvironment, where its expression correlated with genes involved in critical cellular processes. Furthermore, elevated expression has been observed in cervical cancer tissues from surgically-treated patients and in various primary human cervical cancer cells. In vitro functional studies demonstrated that genetic silencing or CRISPR/Cas9-mediated knockout of INTS13 significantly inhibited the proliferation, migration, and invasion of primary cervical cancer cells, while selectively inducing apoptosis. Conversely, ectopic INTS13 overexpression markedly enhanced these malignant phenotypes. Mechanistically, we identified heterogeneous nuclear ribonucleoprotein C (hnRNPC) as a critical downstream effector, with INTS13 regulating hnRNPC expression, and the restoration of hnRNPC effectively reversing the anti-cervical cancer effects observed upon INTS13 silencing. Furthermore, the transcription factor ZNF384 (zinc finger protein 384) was identified as an upstream regulator that directly binds to and positively governs INTS13 expression. Finally, in vivo animal models confirmed that targeted silencing of INTS13 significantly impeded cervical cancer xenograft growth in nude mice, reduced cellular proliferation, and augmented apoptosis, consistently accompanied by a reduction in hnRNPC expression. These findings collectively establish INTS13 as a crucial precancerous gene in cervical cancer, promoting malignant phenotypes primarily through the ZNF384-INTS13-hnRNPC signaling axis.