KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

Abstract

The transcription factor KLF6 has an essential role in the development and metastasis of multiple human cancers. Paradoxically, KLF6 expression was found to be attenuated in primary metastatic clear cell renal cell carcinoma (ccRCC), such that it is unclear how KLF6 affects malignant progression in this setting. In this study, we demonstrate that KLF6 attenuation in renal cells is sufficient to promote E2F1-mediated epithelialmesenchymal transition and metastatic prowess. In a mouse xenograft model of human ccRCC, silencing KLF6 increased tumor cell proliferation and malignant character, whereas E2F1 silencing reversed these properties. These effects were corroborated in a metastatic model system, where we observed a greater number of pulmonary metastatic lesions formed by ccRCC cells where KLF6 was silenced and E2F1 enforced. Analysis of clinical specimens of ccRCC revealed that low levels of KLF6 and high levels of E2F1 correlated closely with ccRCC development. Overall, our results established the significance of activating the KLF6-E2F1 axis in aggressive ccRCC, defining a novel critical signaling mechanism that drives human ccRCC invasion and metastasis. Cancer Res; 77(2); 330-42. Ó2016 AACR.

MicroRNA‑18b acts as an oncogene in gastric cancer by directly targeting Kruppel‑like factor 6

“…KLF6, a zinc finger transcription factor, is frequently downregulated in several types of human cancer, including lung (29), ovarian (30), prostate (31), glioma (32) and colorectal cancer (33). Previous studies have demonstrated that KLF6 contributes to the regulation of various biological processes, including cell proliferation, apoptosis, differentiation, invasion and metastasis (34,35). In GC, the expression level of KLF6 is decreased in tumor tissues compared with normal gastric mucosa (18).…”

RETRACTED: Risk-Associated Long Noncoding RNA FOXD3-AS1 Inhibits Neuroblastoma Progression by Repressing PARP1-Mediated Activation of CTCF

“…7 In this study, we demonstrated that CTCF induced epigenetic inactivation of downstream target genes by recruiting repressive histone marks and attenuating the enrichment of RNA Pol II. These CTCF target genes, such as FOXD3, 32,33 IFIT2, 34 IL6ST, 35 KLF6, 36 and SAMD9, 37 are associated with tumor proliferation, neuronal differentiation, invasion, and metastasis. The consistent association between expression of these genes and patient survival in public datasets further supports their functional roles in NB progression.…”

The E2F1–miR-520/372/373–SPOP Axis Modulates Progression of Renal Carcinoma

“…Numerous studies reveal that E2F1 is equipped with an ability to regulate tumor development in many types of human cancer (49,50). It has been shown that aberrant expression of E2F1 is a key regulator to drive human RCC invasion and metastasis (51,52). Nevertheless, the molecular mechanism by which E2F1 promotes the development of RCC is still unclear.…”