UTX and MLL4 coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells.
Histone methyltransferases and demethylases reversibly modulate histone lysine methylation, which is considered a key epigenetic mark associated with gene regulation. Recently, aberrant regulation of gene expression by histone methylation modifiers has emerged as an important mechanism for tumorigenesis. However, it remains largely unknown how histone methyltransferases and demethylases coregulate transcriptional profiles for cancer cell characteristics. Here, we show that in breast cancer cells, the histone H3 lysine 27 (H3K27) demethylase UTX (also known as KDM6A) positively regulates gene expression programs associated with cell proliferation and invasion. The majority of UTX-controlled genes, including a cohort of oncogenes and prometastatic genes, are coregulated by the H3K4 methyltransferase mixed lineage leukemia 4 (MLL4, also called ALR, KMT2D, and MLL2). UTX interacted with a C-terminal region of MLL4. UTX knockdown resulted in significant decreases in the proliferation and invasiveness of breast cancer cells in vitro and in a mouse xenograft model. Such defective cellular characteristics of UTX-depleted cells were phenocopied by MLL4 knockdown cells. UTX-catalyzed demethylation of trimethylated H3K27 and MLL4-mediated trimethylation at H3K4 occurred interdependently at cotarget genes of UTX and MLL4. Clinically, high levels of UTX or MLL4 were associated with poor prognosis in patients with breast cancer. Taken together, these findings uncover that coordinated regulation of gene expression programs by a histone methyltransferase and a histone demethylase is coupled to the proliferation and invasion of breast cancer cells.
Authors' Affiliations: Department of Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center; Cancer Biology Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas; Graduate Institute of Basic Medical Science, China Medical University, Taichung; and Department of Biotechnology, Asia University, Taichung, Taiwan.
Jae-Hwan
JH
Kim
Amrish
A
Sharma
Shilpa S
SS
Dhar
Sung-Hun
SH
Lee
Bingnan
B
Gu
Chia-Hsin
CH
Chan
Hui-Kuan
HK
Lin
Min Gyu
MG
Lee
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056466:Histone Demethylases / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008745:Methylation; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000502:physiology*; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational
D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; D056466:Histone Demethylases; C523998:KDM6A protein, human; D011495:Histone-Lysine N-Methyltransferase; C530816:MLL4 protein, human