Deletion of mdig enhances H3K36me3 and metastatic potential of the triple negative breast cancer cells

Chitra Thakur; Yiran Qiu; Qian Zhang; Nicholas J Carruthers; Miaomiao Yu; Zhuoyue Bi; Yao Fu; Priya Wadgaonkar; Bandar Almutairy; Akimasa Seno; Paul M Stemmer; Fei Chen

doi:10.1016/j.isci.2022.105057

Deletion of mdig enhances H3K36me3 and metastatic potential of the triple negative breast cancer cells

iScience. 2022 Sep 3;25(10):105057. doi: 10.1016/j.isci.2022.105057. eCollection 2022 Oct 21.

Authors

Chitra Thakur¹, Yiran Qiu¹, Qian Zhang², Nicholas J Carruthers³, Miaomiao Yu^{2

4}, Zhuoyue Bi¹, Yao Fu¹, Priya Wadgaonkar², Bandar Almutairy^{2

5}, Akimasa Seno^{2

6}, Paul M Stemmer³, Fei Chen^{1

2}

Affiliations

¹ Stony Brook Cancer Center and Department of Pathology, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY 11794, USA.
² Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA.
³ Institute of Environmental Health Sciences, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
⁴ Cancer Hospital of China Medical University, 44 Xiaoheyan Road, Dadong District, Shenyang, 110042 Liaoning Province, China.
⁵ College of Pharmacy, Al-Dawadmi Campus, Shaqra University, P.O. Box 11961, Riyadh, Saudi Arabia.
⁶ Faculty of Engineering, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan.

Abstract

In this report, we provide evidence showing diminished expression of the mineral dust-induced gene (mdig), a previously identified oncogenic gene, in human triple negative breast cancer (TNBC). Using a mouse model of orthotopic xenograft of the TNBC MDA-MB-231 cells, we demonstrate that mdig promotes the growth of primary tumors but inhibits metastasis of these cells in vivo. Knockout of mdig resulted in an enhancement of H3K36me3 in the genome and upregulation of some X chromosome-linked genes for cell motility, invasion, and metastasis. Silencing MAGED2, one of the most upregulated and H3K36me3-enriched genes resulted from mdig depletion, can partially reverse the invasive migration of the mdig knockout cells. The anti-metastatic and inhibitory role of mdig on H3K36me3 was cross-validated in another cell line, A549 lung cancer cells. Together, our data suggest that mdig is antagonist against H3K36me3 that enforces expression of genes, such as MAGED2, for cell invasion and metastasis.

Keywords: Cancer; Molecular biology; Molecular mechanism of gene regulation.