Over-expression and knockdown of KLF5

ABSTRACT: Activation of the Ras/Erk pathway upregulates expression of the Kruppel-like Factor 5 (KLF5) transcription factor, and KLF5 is a downstream mediator of Ras oncogenic signaling. Specifically, in bladder and colon cancer cell lines KLF5 upregulates the Ras-pathway target gene cyclin D1, and facilitates entry into the S phase of the cell cycle. Ras mutations are common in lung cancer, but a role for KLF5 in lung tumorigenesis has not been defined. To this end, we manipulated KLF5 expression in four Ras-mutant human lung adenocarcinoma cell lines to find that KLF5 significantly modulates anchorage-independent growth, a mutant Ras phenotype. However, in a mouse model of human lung adenocarcinoma, K-RasG12D does not critically require Klf5 to mediate oncogenesis or induce cyclin D1 expression. Patients with lung tumors expressing high levels of KLF5 have significantly better prognosis than those with low or no KLF5 expression (opposite of mutant Ras prognosis). The latter may be explained by KLF5 transcriptional repression of the ATP-binding cassette, sub-family G (WHITE), member 2 (ABCG2), an anthracycline transporter. In agreement with this, KLF5 knockdown cells display significantly more Hoechst “side population” and resistance to doxorubicin. In summary, while KLF5 is not an obligate partner in Ras oncogenic signaling, KLF5 control of ABCG2 expression is significant to patient survival.

ORGANISM(S): Homo sapiens

PROVIDER: GSE16555 | GEO | 2010/06/23

SECONDARY ACCESSION(S): PRJNA116185

REPOSITORIES: GEO