Key Takeaways & Executive Findings
- •• DNAJC9 is overexpressed in malignant cervical cancer cells and its downregulation inhibits proliferation, induces G1/S arrest, and suppresses tumorigenicity. • GLI1 is a key downstream effector of DNAJC9; GLI1 rescue reverses proliferation defects caused by DNAJC9 knockdown. • DNAJC9 promotes p300-H3 interaction to sustain H3K27ac at the GLI1 enhancer, facilitating GLI1 transcription. • DNAJC9 expression positively correlates with GLI1 in clinical specimens, suggesting the DNAJC9-GLI1 axis as a prognostic marker and therapeutic target.
Abstract
DNAJC9, an HSP40 family member with histone chaperone function, exhibits unclear roles in cervical cancer. DNAJC9 is specifically overexpressed in malignant cervical cancer cells, and downregulation of DNAJC9 inhibits proliferation, induces G1/S arrest, and suppresses tumorigenicity. GLI1 has been identified as a key downstream effector of DNAJC9, and GLI1 rescue reverses proliferation defects. Mechanistically, DNAJC9 promotes the p300-H3 interaction to sustain H3K27ac at the GLI1 enhancer and facilitate GLI1 transcription, driving proliferation. Furthermore, DNAJC9 expression correlates positively with GLI1 in clinical specimens, suggesting that the DNAJC9-GLI1 axis is a potential prognostic marker and therapeutic target.
1. Introduction
Cervical cancer is one of the most common malignant tumors among women worldwide and represents a significant threat to women's health [1]. According to GLOBOCAN 2022 data, there were approximately 662,000 new cases and 349,000 deaths from cervical cancer globally in 2022, with both incidence and mortality ranking as the fourth highest among female malignancies [2,3]. In China, the disease burden of cervical cancer is also showing an upward trend. Women aged 45 years and older have the highest incidence and mortality rates, and due to limitations in HPV vaccination coverage and screening participation, the prevention and control situation for this population is particularly challenging [4]. Therefore, elucidating the molecular mechanisms underlying cervical cancer development and identifying novel diagnostic markers and therapeutic targets are of significant clinical importance.
Cellular proliferation relies on the precise coordination of protein homeostasis, chromatin dynamics, and transcriptional programs [5]. HSP40 (DnaJ) family proteins, as essential co-chaperones of the HSP70 system, not only participate in protein folding but also play important roles in regulating cell proliferation by modulating cell cycle-related proteins and chromatin-associated processes [6]. Among the HSP40 family members, DNAJC9 has been identified as a critical histone chaperone, specifically involved in H3-H4 binding, nuclear transport and nucleosome assembly [7]. By regulating histone availability and chromatin structure establishment, DNAJC9 plays an important role in maintaining transcriptional homeostasis and genomic stability. DNAJC9 deficiency leads to the mislocalization of histones and the variant CENP-A throughout the genome, ultimately resulting in chromatin instability [8]. However, the role of DNAJC9 in tumor development and progression remains unclear. Notably, an early study using gene expression profiling revealed that DNAJC9 was upregulated in patients with cervical cancer and lymph node metastasis, suggesting its potential association with cervical cancer progression [9]. However, to date, the specific function and molecular mechanism of DNAJC9 in cervical cancer proliferation have not been reported.
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XIE Zhongyi, DI Longjiang, HE Xingkai, HUANG Mingzhu, QIAN Jinqin, YANG Hui, CHEN Jiayi, LU Xiaopeng, ZHU Wei-Guo (2026). DNAJC9 promotes cervical cancer cell proliferation by regulating GLI1 expression. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2026080
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Frequently Asked Questions
What is the role of DNAJC9 in cervical cancer?
DNAJC9 is overexpressed in malignant cervical cancer cells and promotes proliferation by regulating GLI1 expression. Downregulation of DNAJC9 inhibits proliferation, induces G1/S arrest, and suppresses tumorigenicity.
How does DNAJC9 regulate GLI1 expression?
DNAJC9 promotes the interaction between p300 and histone H3, sustaining H3K27ac at the GLI1 enhancer, which facilitates GLI1 transcription and drives proliferation.
What is the clinical significance of the DNAJC9-GLI1 axis?
DNAJC9 expression positively correlates with GLI1 in clinical specimens, suggesting that the DNAJC9-GLI1 axis could serve as a prognostic marker and therapeutic target for cervical cancer.
What are the downstream effects of GLI1 in cervical cancer?
GLI1 promotes cell cycle progression by upregulating genes such as Cyclin D1, c-Myc, and FOXM1, driving G1/S transition and tumor cell proliferation.
What is the novelty of this study?
This study identifies DNAJC9 as a histone chaperone that regulates GLI1 expression through epigenetic mechanisms, providing new insights into cervical cancer pathogenesis and potential therapeutic strategies.
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