Products Cited in Publications Worldwide Regulation of Cell Cycle Progression by Keratin 19 in Breast Cancer Cells

Regulation of Cell Cycle Progression by Keratin 19 in Breast Cancer Cells

Sharma, Pooja

Abstract

Keratins are widely used as diagnostic markers to detect tumors in both primary and distal sites and to determine tumors’ tissue of origin in order to aid in treatment strategies. In this regard, K19 has been particularly useful because it is among the most sensitive diagnostic markers across a broad range of cancer types. K19 has also been shown to be one of the most reliable prognostic markers for multiple tumor types, including breast cancer where higher expression of K19 is correlated with worse patient survival. Despite the clinical data showing positive correlation between increased K19 expression and poor survival rates among patients of breast cancer types, the role of K19 in breast cancer remains unclear. To understand the role of K19 in breast cancer, we generated KRT19 knockout (KO) cell lines using MCF7 and MDA-MB-231 breast cancer cell lines. Using this system, we found that KRT19 KO cells exhibit reduced proliferation compared to parental control cells and uncovered a cell cycle promoting role of K19. We identified that K19 promotes proliferation of cancer cells by stabilizing a cell cycle regulator cyclin D3. However, how a cytoskeletal protein regulates levels of cyclin D3 remained unknown. It has been known that GSK3β play a crucial role in degrading cyclin D3 for proteasomal degradation. In our study in MCF7 cells, we identified GSK3β as a keratin-interacting protein and found that K19 suppressed GSK3β activity by inhibiting its nuclear accumulation. GSK3β-binding by K19 required serine 10 and 35 residue as K19 S10A or S35A mutation failed to protect cyclin D3 from protein degradation. Our results reveal a novel regulatory role of K19 on GSK3β localization and activity as a mechanism of how a cytoskeletal protein stabilizes a cell cycle regulator and promotes proper cell proliferation. In addition, we found that K19 expressing cells are more sensitive to cyclin dependent kinase (CDK) 4/6 inhibitors as compare to KRT19 KO cells. The sensitivity of KRT19 KO cells to CDK4/6 inhibitor was increased when cotreated with a GSK3β inhibitor, demonstrating that the K19-GSK3β axis plays a critical role in drug resistance. Given that K19 expression levels are frequently elevated in various cancers, K19 can be used to predict the efficacy of CDK4/6 inhibitors and patients may be cotreated with a GSK3β inhibitor to avoid drug resistance.

Purchased from AmBeed

LY294002

A133122154447-36-698%

LY294002

15.0/1mg

Detail