YY1 Promotes Telomerase Activity and Laryngeal Squamous Cell Carcinoma Progression Through Impairment of GAS5-Mediated p53 Stability

Abstract

Yin Yang 1 (YY1) is a key transcription factor that exerts functional roles in the cell biological process of various cancers. The current study aimed to elucidate the role and mechanism of YY1 in laryngeal squamous cell carcinoma (LSCC). YY1 mRNA and protein expression in human LSCC cell lines was detected by RT-qPCR and Western blot analysis. An interaction of YY1, GAS5, and p53 protein stability was predicted and confirmed by bioinformatics, ChIP, Co-IP, RIP, and FISH assays. Following loss- and gain-function assays, LSCC cell proliferation, colony formation, cell cycle, telomere length and telomerase activity were evaluated by CCK-8 assay, colony formation assay, flow cytometry, and PCR-ELISA, respectively. Nude mice were xenografted with the tumor in vivo. LSCC cell lines presented with upregulated expression of YY1, downregulated GAS5 expression, and decreased p53 stability. YY1 inhibited the expression of GAS5, which in turn recruited p300 and bound to p53, thus stabilizing it. Moreover, YY1 could directly interact with p300 and suppressp53 stability, leading to enhancement of cell proliferation, telomere length and telomerase activity in vitro along with tumor growth in vivo. Collectively, YY1 can stimulate proliferation and telomerase activity of LSCC cells through suppression of GAS5-dependent p53 stabilization or by decreasing p53 stability via a direct interaction with p300, suggesting that YY1 presents a therapeutic target as a potential oncogene in LSCC development and progression.

CK2 and the Hallmarks of Cancer

“…Beyond that, CK2 seems to participate in the regulation of Yin Yang 1 (YY1), a ubiquitously expressed multifunctional zinc finger transcription factor. YY1 is often overexpressed in cancers and is involved in the regulation of tumor cell growth, proliferation, migration, and metastasis [ 218 , 219 ]. It can directly bind to the promoter region of multiple long non-coding RNAs to regulate their expression, and has been shown to inhibit the activation of p53 in response to genotoxic stress [ 220 ], and to decrease p53 stability [ 218 ].…”

“…YY1 is often overexpressed in cancers and is involved in the regulation of tumor cell growth, proliferation, migration, and metastasis [ 218 , 219 ]. It can directly bind to the promoter region of multiple long non-coding RNAs to regulate their expression, and has been shown to inhibit the activation of p53 in response to genotoxic stress [ 220 ], and to decrease p53 stability [ 218 ]. Riman et al provided evidence that CK2α phosphorylates YY1 in vivo at Ser118 in its transactivation domain, proximal to a caspase 7 cleavage site thereby preventing YY1s cleavage during apoptosis [ 221 ].…”

RBM14 as a novel epigenetic-activated tumor oncogene is implicated in the reprogramming of glycolysis in lung cancer

“…Gao et al indicate that YY1 interacts with spleen tyrosine kinase and inhibits SNAI2 transcription in lung cancer cells [ 23 ]. Wei et al suggest that YY1 directly interacts with p300 and suppresses p53 stability, leading to the enhancement of cell proliferation and tumor growth [ 24 ]. KDM6A is recruited to the NTRK1 promoter by YY1 with subsequent enhancing NTRK1-encoded protein expression [ 25 ].…”

PLAU is associated with cell migration and invasion and is regulated by transcription factor YY1 in cervical cancer

“…There are unclear details about YY1 regulating PLAU. YY1 can regulate target genes with various co-factors, such as p300 and HDAC1 (38)(39)(40); however, whether YY1 regulates PLAU expression needing such co-factors remains unknown.…”