Yin Yang 1-Induced Long Noncoding RNA DUXAP9 Drives the Progression of Oral Squamous Cell Carcinoma by Blocking CDK1-Mediated EZH2 Degradation

Wenkai Zhou; Yisheng Feng; Chengzhong Lin; Chi Kuan Chao; Ziqi He; Shiyao Zhao; Jieyuan Xue; Xu-Yun Zhao; Wei Cao

doi:10.1002/advs.202207549

Yin Yang 1-Induced Long Noncoding RNA DUXAP9 Drives the Progression of Oral Squamous Cell Carcinoma by Blocking CDK1-Mediated EZH2 Degradation

Adv Sci (Weinh). 2023 Sep;10(25):e2207549. doi: 10.1002/advs.202207549. Epub 2023 Jul 3.

Authors

Wenkai Zhou^{1

2}, Yisheng Feng², Chengzhong Lin^{2

3}, Chi Kuan Chao², Ziqi He², Shiyao Zhao², Jieyuan Xue⁴, Xu-Yun Zhao⁵, Wei Cao^{1

2}

Affiliations

¹ Department of Oral and Maxillofacial & Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
² National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, China.
³ The 2nd Dental Center, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, 200011, China.
⁴ Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
⁵ Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

Abstract

LncRNAs play a critical role in oral squamous cell carcinoma (OSCC) progression. However, the function and detailed molecular mechanism of most lncRNAs in OSCC are not fully understood. Here, a novel nuclear-localized lncRNA, DUXAP9 (DUXAP9), that is highly expressed in OSCC is identified. A high level of DUXAP9 is positively associated with lymph node metastasis, poor pathological differentiation, advanced clinical stage, worse overall survival, and worse disease-specific survival in OSCC patients. Overexpression of DUXAP9 significantly promotes OSCC cell proliferation, migration, invasion, and xenograft tumor growth and metastasis, and upregulates N-cadherin, Vimentin, Ki67, PCNA, and EZH2 expression and downregulates E-cadherin in vitro and in vivo, whereas knockdown of DUXAP9 remarkably suppresses OSCC cell proliferation, migration, invasion, and xenograft tumor growth in vitro and in vivo in an EZH2-dependent manner. Yin Yang 1 (YY1) is found to activate the transcriptional expression of DUXAP9 in OSCC. Furthermore, DUXAP9 physically interacts with EZH2 and inhibits EZH2 degradation via the suppression of EZH2 phosphorylation, thereby blocking EZH2 translocation from the nucleus to the cytoplasm. Thus, DUXAP9 can serve as a promising target for OSCC therapy.

Keywords: EZH2; LncRNA DUXAP9; Yin Yang 1 (YY1); oral squamous cell carcinoma; ubiquitination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CDC2 Protein Kinase
Carcinoma, Squamous Cell* / metabolism
Cell Line, Tumor
Cell Proliferation / genetics
Enhancer of Zeste Homolog 2 Protein / genetics
Head and Neck Neoplasms*
Humans
Mouth Neoplasms* / genetics
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
Squamous Cell Carcinoma of Head and Neck / genetics
Yin-Yang

Substances

RNA, Long Noncoding
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
CDK1 protein, human
CDC2 Protein Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding