Contribution of LATS1 and LATS2 promoter methylation in OSCC development

Abstract

The aberrant DNA methylation of the tumor suppressor genes involved in DNA Damage Response (DDR) signaling and cell cycle regulation may lead to the tumorigenesis.Our purpose here is to analyze the promoter methylation and mRNA expression levels of LATS1 and LATS2 (LATS1/2) genes in OSCC. Promoter methylation status of LATS1/2 genes was evaluated in 70 OSCC paraffin-embedded tissues and 70 normal oral samples, using Methylation Specific PCR (MSP). LATS1/2 mRNA expression profiles were also investigated in 14 OSCC patients and 14 normal samples, using real-time PCR. In both candidate genes, promoter methylation assessment revealed significant relationship between cases and controls (OR = 2.24, 95 % CI = 1.40-3.54, P = 0.001; LATS1 and OR = 15.5, 95%CI = 3.64-64.76, P < 0.001; LATS2). As well as, the evaluation of mRNA expression levels showed decreased expression in OSCC tissues in compare to control tissues. (Mean ± SD 1.74 ± 0.14 in OSCC versus 2.10 ± 0.24 in controls, P < 0.001; LATS1 and Mean ± SD 1.36 ± 0.077 in OSCC versus 1.96 ± 0.096 in controls, P < 0.001; LATS2). To the best our knowledge, this is the first report regarding the down-regulation of LATS1/2 through promoter methylation in OSCC. It is suggested to explore the down-stream transcription factors of both genes for finding the molecular mechanism of this deregulation in OSCC.

circRNA_0000140 suppresses oral squamous cell carcinoma growth and metastasis by targeting miR-31 to inhibit Hippo signaling pathway

“…For example, aberrant LATS2 overexpression has been observed and associated with aggressive features and unfavorable survival incolorectal cancer 35 , non-small-cell lung cancer 36 , and gallbladder cancer 37 . In the context of OSCC, LATS2 has been reported to inhibit cell proliferation and invasion by phosphorylating YAP, or act through promoter methylation 13,14 . While overexpression of miR-31 was shown to play an oncogenic role by repressing expression of LATS2, little is known about the role of miR-31/LATS2 signaling in regulating OSCC cells 38 .…”

“…For instance, LATS2 was reported to increase cell invasive capacities of metastasis via harboring mutant p53, leading to increased SNAIL1 stability in breast cancer 12 . In OSCC, lower LATS2 expression was observed in OSCC patients 13 , and overexpression of LATS2 blocked cell proliferation, colony formation, and cell invasion in vitro, and xenografts in vivo 14 . Therefore, understanding the molecular mechanism of LATS2-mediated Hippo pathway in OSCC will provide significant information for the treatment of OSCC.…”

The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway

“…70 Such mode of inactivation has been documented for LATS1, [71][72][73] LATS2, 74,75 and in some cases for both, in various types of tumors. [76][77][78][79][80][81][82] Importantly, downregulation of LATS expression has been associated with more aggressive cancer phenotypes. 74,[76][77][78]83 Promoter silencing can be mediated also by long non-coding RNAs (lncRNAs), which recruit the epigenetic machinery.…”

KRT84 is a potential tumor suppressor and good prognosis signature of oral squamous cell carcinoma

“…DNA methylation was previously reported to down-regulate the promoter activity of human cathelicidin antimicrobial peptide (CAMP) gene, which was associated with the carcinogenesis of OSCC [13]. Besides, the down-regulations of LATS1/2 genes caused by promoter methylation were also observed in OSCC patients [14]. Although numerous genetic biomarkers were identified, the knowledge on the detailed biological function and in-depth analysis are still limited for many of them [15], and some of the researches mixed the primary sites of OSCC.…”