The kinesin-8 member Kif19 alters microtubule dynamics, suppresses cell adhesion, and promotes cancer cell invasion

Abstract

AbstractMetastasis is one of the deadliest aspects of cancer. Initial Metastatic spread is dependent on the detachment and dissemination of cells from a parent tumor, and invasion into the surrounding tissue. In this study, we characterize the kinesin-8 member Kif19 as a promoter of cancer cell invasion that suppresses cell-cell adherens junctions and cell-matrix focal adhesions. Initial analysis of publicly available cancer patient data sets demonstrated that Kif19 expression correlates with worse overall survival probability in several cancers and that Kif19 expression is increased in metastases of colorectal and breast carcinoma compared to the primary tumor. Depletion of Kif19 from two human cancer cell lines (DMS53 and MDA-MB-231) did not alter viability, but decreased the cells’ ability to invade a Matrigel matrix by half and impaired the invasion of spheroids into a primary cell monolayer. Ectopically expressed Kif19 localized to, and partially depolymerized, microtubules in the cell periphery. However, Kif19 depletion increased microtubule dynamicity and sensitivity to pharmacological depolymerization without altering total microtubule polymer levels. These data indicate that Kif19 can both depolymerize and stabilize microtubules. Given this activity, we then studied Kif19’s effect on focal adhesions and adherens junctions, which are both regulated by microtubule dynamics. Kif19 knockdown increased the proportion of cell surface area covered by Vinculin focal adhesions. Further, Kif19 depletion increased whole cell E-cadherin expression and the accumulation of E-cadherin at cell-cell adherens junctions. Conversely, ectopic overexpression of full-length Kif19 led to proportionally smaller focal adhesions and impaired E-cadherin accumulation at cell-cell junctions. Our current hypothesis is that aberrant Kif19 expression in cancer alters focal adhesion dynamics and suppresses E-cadherin expression, which enhance cell invasiveness. Further, we propose that these changes in cell adhesion are due to modification of peripheral microtubule dynamics by Kif19, potentially through disruption of local rho GTPase activity.