A 42 kb region on human chromosome 9p21 encodes for three distinct tumor 
suppressors, p16(INK4A), p14(ARF) and p15(INK4B), and is altered in an estimated 
30-40% of human tumors. The expression of the INK4A-ARF-INK4B gene cluster is 
silenced by polycomb during normal cell growth and is activated by oncogenic 
insults and during aging. How the polycomb is recruited to repress this gene 
cluster is unclear. Here, we show that expression of oncogenic Ras, which 
stimulates the expression of p15(INK4B) and p16(INK4A), but not p14(ARF), 
inhibits the expression of ANRIL (antisense non-coding RNA in the INK4 locus), a 
3.8 kb-long non-coding RNA expressed in the opposite direction from 
INK4A-ARF-INK4B. We show that the p15(INK4B) locus is bound by SUZ12, a 
component of polycomb repression complex 2 (PRC2), and is H3K27-trimethylated. 
Notably, depletion of ANRIL disrupts the SUZ12 binding to the p15(INK4B) locus, 
increases the expression of p15(INK4B), but not p16(INK4A) or p14(ARF), and 
inhibits cellular proliferation. Finally, RNA immunoprecipitation demonstrates 
that ANRIL binds to SUZ12 in vivo. Collectively, these results suggest a model 
in which ANRIL binds to and recruits PRC2 to repress the expression of 
p15(INK4B) locus.