Oral squamous cell carcinoma(OSCC)is widely represented as a heterogeneous malignant tumor with more aggressive phenotypes,but the basis for these characteristics remains unknown.In the current study,we show that up-regulation of the Polycomb complex histone methytransferase EZH2 is critical to maintain the malignant phenotypes in OSCC and associated significantly with oral squamous cell carcinoma development in patients with oral leukoplakia(OLP),which represents oral precancerous lesion as well as the worse prognosis of patients with locally advanced OSCC.Patients with OLP(n=76)and OSCC (n=124)from two independent cohort were included in this study.Immunohistochemical analyses on EZH2 in the two cohorts revealed that the higher EZH2 levels were strongly associated with dysplasia(P<0.001)and OSCC development(P<0.0001)in patients with OLP,as well as worse overall survival(P=0.001)and disease free survival(P=0.002)in patients with locally advanced OSCC.Furthermore,upon EZH2 silencing by small interfering RNA(siRNA)-mediated knockdown,the proliferation,anchorage-independent growth and invasion potential of OLP cell line and OSCC cell lines were remarkably suppressed.Available publicly H3K27 modifications based on CpG array and three public microarray datasets (GEO)analyses identified human four-and-half LIM protein 1(FHL1)as a novel candidate target of EZH2 in OSCC.Further depletion of EZH2 by RNA interference(RNAi),the expression of FHL1 was notably restored in OLP and OSCC cell lines.In addition,ablation of FHL1 by RNA interference promoted significantly proliferation and invasion potential of OSCC cells.Together,our findings indicate that aberrantly elevated EZH2 promotes aggressive phenotypes of OLP and OSCC cells and plays a critical role in initiation and progression of OSCC.meanwhile,FHL1 may be a novel target of EZH2 for transcriptional repression in OSCC initiation and progression.