miR-34a, miR-424 and miR-513 inhibit MMSET expression to repress endometrial cancer cell invasion and sphere formation

// Peixin Dong 1, * , Ying Xiong 2, * , Junming Yue 3, 4 , Sharon J.B. Hanley 5 and Hidemichi Watari 1 1 Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan 2 Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China 3 Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA 4 Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA 5 Department of Women’s Health Educational System, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan * These authors contributed equally to this work Correspondence to: Peixin Dong, email: dpx1cn@gmail.com Hidemichi Watari, email: watarih@med.hokudai.ac.jp Keywords: microRNA-34a; microRNA-424; microRNA-513; MMSET; endometrial cancer metastasis Received: March 24, 2018      Accepted: April 16, 2018      Published: May 01, 2018 ABSTRACT Although the oncogene MMSET (also known as NSD2 or WHSC1) has an essential role in malignancies, its impact on human endometrial cancer (EC) metastasis and the molecular mechanism of MMSET regulation are largely unknown. We report that MMSET was markedly upregulated in EC cell lines and EC tissues, and was significantly associated with poor survival in EC. MMSET overexpression greatly promoted EC cell invasion and sphere formation, whereas inhibition of MMSET reduced EC cell invasion and sphere formation. Importantly, Twist1 was required for MMSET-induced EC cell invasion and sphere formation. Moreover, we demonstrate that miR-34a, miR-424 and miR-513 directly modulate MMSET expression to attenuate the invasion and sphere formation capacity of EC cells. miR-34a, miR-424 and miR-513 were down-regulated in EC compared with normal tissue, and reduced expression of miR-34a, miR-424 and miR-513 was clinically associated with a poorer prognosis in EC patients. Furthermore, specific inhibition of MMET with BIX-01294 led to decreased EC cell invasion and impaired sphere formation. These findings suggest a pro-metastatic role for MMSET in EC and reveal that the repression of miR-34a, miR-424 and miR-513 contributes to the overexpression of MMSET during EC metastasis.