CDK8 Inhibition Increases E2F1 Transcriptional Activity and Promotes STAT3-Dependent Suppression of Mcl-1 in Triple-Negative Breast Cancer Cell Line MDA-MB-468

TL;DR

Inhibiting CDK8 in triple-negative breast cancer cells increases E2F1 activity and reduces Mcl-1, an antiapoptotic protein, through a mechanism involving STAT3.

Contribution

This study reveals a novel mechanism by which CDK8 inhibition modulates apoptosis-related proteins via E2F1 and STAT3 in triple-negative breast cancer.

Findings

CDK8 inhibition reduces phosphorylation of E2F1 and STAT3 in MDA-MB-468 cells.

CDK8 inhibition increases p73 expression and decreases Mcl-1 expression.

STAT3 knockdown opposes CDK8 inhibition's effect on Mcl-1.

Abstract

The targeting of cyclin dependent kinase 8 (CDK8) as a potential strategy for cancer treatment has been of interest since the identification of CDK8 as an oncogene product. In this report, we communicate the results of our continuing investigation into the effects of CDK8 inhibitor on triple-negative breast cancer cell line MDA-MB-468. Here, we demonstrate that inhibition of CDK8 decreases phosphorylation of CDK8 substrates E2 promoter binding factor 1 (E2F1) at serine 375 and signal transducer and activator of transcription 3 (STAT3) at serine 727 in these cells. Additionally, luciferase expression was increased in E2F1-responsive luciferase plasmid-transfected cells. Expression of E2F1 transcription target, the proapoptotic protein p73, was increased, and expression of antiapoptotic protein myeloid cell leukemia sequence 1 (Mcl-1) was decreased in CDK8 inhibitor-treated cells. We also demonstrate that knockdown of STAT3 or disruption of STAT3 function in MDA-MB-468 cells opposes the effects of CDK8 inhibition on Mcl-1. Together, these results suggest that CDK8 inhibitor treatment can modulate the expression of apoptosis-related proteins p73 and Mcl-1 and continues to highlight the potential cooperative effects of E2F1 and STAT3 in the activity of CDK8 inhibitor against MDA-MB-468 triple-negative breast cancer cells.

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