KLF8 overexpression

KLF8 levels are associated with chemoresistance in triple negative breast cancer patients and overexpression in breast cancer cells increased paclitaxel resistance. KLF8 and OGT co-regulate each other to form a feed-forward loop to promote CSCs phenotype and mammosphere formation of breast cancer cells. These results suggest a critical role of KLF8 and OGT in promoting CSCs and cancer progression, that may serve as potential targets for developing strategy to target CSCs specifically.

Using promoter-luciferase reporter assays, we defined that upon TGF-β1 activation, phosphorylated Smad2 binds and promotes the KLF8 promoter activity, and knockdown of Smad2 inhibits KLF8 promoter activation. Together, these results demonstrate that TGF-β1 activates KLF8 expression by the Smad2 pathway, and KLF8 contributes to OC progression and may serve as a potential therapeutic strategy for treating OC patients.

Furthermore, overexpression of KLF8 showed increase in resistance to paclitaxel in triple-negative breast cancer cells in vitro, suggesting a possible role of KLF8 in promoting chemotherapy resistance in breast cancer. Together, our results suggested that KLF8 and OGT may work in concert in promoting breast cancer stem-like cells population.

Mechanistically, we found that the activated FAK was recruited to the nascent FLPs and that proliferation of the cells was completely prevented with a FAK-specific inhibitor. Taken together, these results shed new light on the role of KLF8 in promoting breast cancer recurrence, the fatal episode of the disease, by inducing CXCR4-dependent FLP formation.

We also found that KLF8 or CXCR4 overexpression strongly enhanced formation of filopodium-like protrusions and proliferation via CXCR4 stimulation in a 3D culture model mimicking the colonization step of metastasis. Taken together, these results suggest that the chemo-induction of KLF8 upregulation be critical for drug resistance and systemic metastasis through enhanced tumor angiogenesis and colonization via CXCR4 over-activation and that KLF8-CXCR4 signaling axis may be a new therapeutic target for drug-resistant breast cancer metastasis.