The Janus-faced roles of Krüppel-like factor 4 in oral squamous cell carcinoma cells

Abstract

Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor that regulates many essential processes, including development and cell differentiation, proliferation, and apoptosis. Along with these roles in normal cells and tissues, KLF4 has important tumor suppressive and oncogenic functions in some malignancies. However, the roles of KLF4 in oral squamous cell carcinoma remain unclear. This study investigated the epigenetic alterations and possible roles of KLF4 in oral cancer carcinogenesis. Notably, KLF4 expression was significantly decreased in human oral cancer tissues compared with healthy controls, and KLF4 promoter hypermethylation contributed to the suppression of KLF4 expression. KLF4 expression was associated with tumor grade. Its expression was much lower in poorly differentiated oral cancers than in well-differentiated cancer cells. KLF4 exerted its antitumor activity in vitro and/or in vivo by inhibiting cell proliferation, cell cycle progression, cell colony formation and by inducing apoptosis. In addition, KLF4 over-expression promoted oral cancer cell migration and invasion in vitro. Knockdown of KLF4 promoted oral cancer cells growth and colony formation, and simultaneously inhibited cell migration and invasion. Mechanistic studies revealed that MMP-9 might contribute to KLF4-mediated cell migration and invasion. These results provide evidence that KLF4 might play Janus-faced roles in oral cancer carcinogenesis, acting both as a tumor suppressor and as an oncogene.

Krüppel-like factor 4 (KLF4): What we currently know

“…In the skin, overexpression of KLF4 results in hyperplasia and dysplasia, eventually leading to the development of squamous cell carcinoma (137). It was also reported that in oral carcinogenesis KLF4 can act either as a tumor suppressor or an oncogene (138). Whether KLF4 acts as a tumor suppressor or an oncogene is likely determined by differences in cellular context, expression patterns of other genes and the chromatin environment of individual cells.…”

Epigenetics of oral and oropharyngeal cancers (Review)

“…The activity and expression of KLF4 are often associated with mutation in various cancers (71)(72)(73)(74). Li et al (75), identified that KLF4 was downregulated in OSCC, and its downregulation correlated with cancer differentiation i.e., the poorer the cancer differentiation, the lower the expression of KLF. The downregulation of KLF4 in OSCC has been associated with promoter hypermethylation (75).…”

Network‑based identification of signature genes KLF6 and SPOCK1 associated with oral submucous fibrosis

“…It primarily works by enhancing p21 expression by a pathway independent of p53, and hence acts as a tumor-suppressor gene (58). It is downregulated in several human cancers and its reduced expression has been correlated with cellular proliferation and poor prognosis in oral cancer (59). One of the studies has demonstrated its role in metastasis and EMT (60).…”