2. Academic Validation
  3. HOMER3 drives oral squamous cell carcinoma progression through TRPV6 calcium influx and TUBB3 microtubule stabilization

HOMER3 drives oral squamous cell carcinoma progression through TRPV6 calcium influx and TUBB3 microtubule stabilization

  • Oncogene. 2026 Jan;45(2):278-294. doi: 10.1038/s41388-025-03611-w.
Chenghui Xu # 1 2,  Jie Zhang # 1 2,  Han Zhang 1 2,  Lan Chen 1 2,  Jinchao Zhao 1 2,  Guizhu Yang 1 2,  Ranran Xiao 1 2,  Jiayan Zhu 1 2,  Chengting Fan 1 2,  Yanli Yao 3 4,  Shuyang Sun 5 6
Affiliations

Affiliations

  • 1 Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University, Shanghai, China.
  • 2 National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology; Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai, China.
  • 3 Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University, Shanghai, China. [email protected].
  • 4 National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology; Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai, China. [email protected].
  • 5 Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University, Shanghai, China. [email protected].
  • 6 National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology; Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41326663 DOI: 10.1038/s41388-025-03611-w
Abstract

Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy characterized by extensive extracellular matrix (ECM) remodeling and microtubule dynamics, which drive tumor progression and therapeutic resistance. Here, we identify HOMER3 as a novel and pivotal regulator that integrates ECM stiffness and microtubule dynamics to promote OSCC malignancy. HOMER3 expression follows a distinct gradient, increasing from low levels in normal tissues to elevated levels in oral leukoplakia and highest levels in OSCC, with high expression significantly associated with advanced stages and poor survival. Mechanistically, HOMER3 acts as a scaffold protein forming two distinct functional complexes: HOMER3-CAMKK1-TRPV6, which mediates calcium influx and activates AMPK/Akt/mTOR and B-Raf/MEK/ERK pathways to promote proliferation, invasion, and ECM remodeling; and HOMER3-CAMKK1-TUBB3, which regulates microtubule dynamics and drives resistance to the chemotherapeutic agent docetaxel. Functional studies reveal that HOMER3 overexpression enhances ECM stiffness, type I Collagen deposition, and Aβ accumulation in the tumor stroma, leading to tumor growth and aggressiveness, while HOMER3 knockdown reduces ECM stiffness, disrupts Collagen composition, and increases sensitivity to docetaxel. These findings establish HOMER3 as a pivotal regulator of OSCC malignancy and chemoresistance, providing novel insights into its role in orchestrating the tumor microenvironment and identifying it as a promising therapeutic target for OSCC.

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