Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis.
Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodelling activities. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumours and metastases, and HOTAIR expression level in primary tumours is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb repressive complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings indicate that lincRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
Gupta
Rajnish A
RA
Howard Hughes Medical Institute and Program in Epithelial Biology, California 94305, USA.
Shah
Nilay
N
Wang
Kevin C
KC
Kim
Jeewon
J
Horlings
Hugo M
HM
Wong
David J
DJ
Tsai
Miao-Chih
MC
Hung
Tiffany
T
Argani
Pedram
P
Rinn
John L
JL
Wang
Yulei
Y
Brzoska
Pius
P
Kong
Benjamin
B
Li
Rui
R
West
Robert B
RB
van de Vijver
Marc J
MJ
Sukumar
Saraswati
S
Chang
Howard Y
HY
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002843:Chromatin / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005801:Genes, Homeobox / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000235:genetics*; D009368:Neoplasm Transplantation; D063146:Polycomb-Group Proteins; D011379:Prognosis; D034622:RNA Interference; D022661:RNA, Untranslated / Q000096:biosynthesis / Q000235:genetics*; D012097:Repressor Proteins / Q000032:analysis / Q000378:metabolism; D015996:Survival Rate
D002843:Chromatin; D006657:Histones; D063146:Polycomb-Group Proteins; D022661:RNA, Untranslated; D012097:Repressor Proteins
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