NDY1/KDM2B Functions as a Master Regulator of Polycomb Complexes and Controls Self-Renewal of Breast Cancer Stem Cells

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 14; pp. 3935 - 3946
• Main Authors: KOTTAKIS, Filippos, FOLTOPOULOU, Parthena, MCNIEL, Elizabeth, KUPERWASSER, Charlotte, TSICHLIS, Philip N, SANIDAS, Ioannis, KELLER, Patricia, WRONSKI, Ania, DAKE, Benjamin T, EZELL, Scott A, ZHU SHEN, NABER, Stephen P, HINDS, Philip W
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.07.2014
• Subjects: Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Proliferation; Enhancer of Zeste Homolog 2 Protein; F-Box Proteins - genetics; F-Box Proteins - metabolism; Female; Gene Expression; Gene Knockdown Techniques; Gynecology. Andrology. Obstetrics; Humans; Immunophenotyping; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; Mammary gland diseases; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplastic Stem Cells - metabolism; Pharmacology. Drug treatments; Phenotype; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Polycomb-Group Proteins - chemistry; Polycomb-Group Proteins - metabolism; Protein Subunits - metabolism; RNA Interference; Tumors; Mammary gland diseases; Self renewal; Breast disease; PcG gene; Stem cell; Self control; Breast cancer; Malignant tumor; Regulator; Tumor cell; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-13-2733

The JmjC domain histone H3K36me2/me1 demethylase NDY1/KDM2B is overexpressed in various types of cancer. Here we show that knocking down NDY1 in a set of 10 cell lines derived from a broad range of human tumors inhibited their anchorage-dependent and anchorage-independent growth by inducing senescence and/or apoptosis in some and by inhibiting G1 progression in all. We further show that the knockdown of NDY1 in mammary adenocarcinoma cell lines decreased the number, size, and replating efficiency of mammospheres and downregulated the stem cell markers ALDH and CD44, while upregulating CD24. Together, these findings suggest that NDY1 is required for the self-renewal of cancer stem cells and are in agreement with additional findings showing that tumor cells in which NDY1 was knocked down undergo differentiation and a higher number of them is required to induce mammary adenocarcinomas, upon orthotopic injection in animals. Mechanistically, NDY1 functions as a master regulator of a set of miRNAs that target several members of the polycomb complexes PRC1 and PRC2, and its knockdown results in the de-repression of these miRNAs and the downregulation of their polycomb targets. Consistent with these observations, NDY1/KDM2B is expressed at higher levels in basal-like triple-negative breast cancers, and its overexpression is associated with higher rates of relapse after treatment. In addition, NDY1-regulated miRNAs are downregulated in both normal and cancer mammary stem cells. Finally, in primary human breast cancer, NDY1/KDM2B expression correlates negatively with the expression of the NDY1-regulated miRNAs and positively with the expression of their PRC targets.