NDY1/KDM2B functions as a master regulator of polycomb complexes and controls self-renewal of breast cancer stem cells.
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.
Authors' Affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
Filippos
F
Kottakis
Authors' Affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
Parthena
P
Foltopoulou
Authors' Affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
Ioannis
I
Sanidas
Authors' Affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
Patricia
P
Keller
Authors' Affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
Ania
A
Wronski
Authors' Affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
Benjamin T
BT
Dake
Authors' Affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
Scott A
SA
Ezell
Authors' Affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
Zhu
Z
Shen
Authors' Affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
Stephen P
SP
Naber
Authors' Affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
Philip W
PW
Hinds
Authors' Affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
Elizabeth
E
McNiel
Authors' Affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
Charlotte
C
Kuperwasser
Authors' Affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts ptsichlis@tuftsmedicalcenter.org.
Philip N
PN
Tsichlis
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000071221:Enhancer of Zeste Homolog 2 Protein; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D016130:Immunophenotyping; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010641:Phenotype; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000737:chemistry / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D034622:RNA Interference
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; C116662:PRC1 protein, human; D063146:Polycomb-Group Proteins; D021122:Protein Subunits; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2