Histone Demethylase KDM3A Promotes Cervical Cancer Malignancy Through the ETS1/KIF14/Hedgehog Axis

Background: Lysine demethylase 3A (KDM3A) has been increasingly recognized as an important epigenetic regulator involved in Cancer development. This study aims to explore the relevance of KDM3A to cervical Cancer (CC) progression and the molecules involved.

Materials and methods: Tumor and the adjacent tissues from CC patients were collected. KDM3A expression in tissues and CC cell lines and its correlation with the survival and prognosis of patients were determined. Malignant potentials of CC cells and the angiogenesis ability of HUVECs were measured to evaluate the function of KDM3A on CC progression. The interactions among KDM3A, H3K9me2 and ETS1, and the binding between ETS1 and KIF14 were validated through ChIP and luciferase assays. Altered expression of ETS1 and KIF14 was introduced to explore their roles in CC development.

Results: KDM3A was abundantly expressed in CC tissues and cells and linked to dismal prognosis of CC patients. Knockdown of KDM3A suppressed malignant behaviors of CC cells. KDM3A was found to increase ETS1 expression through the demethylation of H3K9me2. Overexpression of ETS1 blocked the inhibiting roles of sh-KDM3A. ETS1 could bind to the promoter region of KIF14 to trigger its transcription. Overexpression ofKIF14aggravated the malignant behaviors of CC cells and the angiogenesis ability of HUVECs, and it activated the Hedgehog signaling pathway. Artificial activation of Hedgehog by Sag1.5 diminished the effects of sh-KDM3A. These changes were reproduced in vivo.

Conclusion: This study evidenced that KDM3A promotes ETS1-mediated KIF14 transcription to promote CC progression with the involvement of the Hedgehog activation.