Premature cleavage and polyadenylation in the minor intron of PTEN modulate its expression and generate a functional...

The tumor suppressor, PTEN, contains a minor intron (mi-INTs) at the start of the gene. mi-INTs regulate the expression of their host genes because their inefficient splicing can be rate-limiting. Whether the PTEN mi-INTs regulate PTEN expression is unclear. PTEN levels are tightly controlled in cancer cells, especially breast cancer, since small reductions promote tumorigenesis. Cancer cells, therefore, employ numerous mechanisms to reduce PTEN. Here, we describe a previously unexplored mechanism that modulates PTEN through its mi-INT. In breast cancer cells, this intron shows low splicing efficiency, causing about half of the PTEN pre-mRNA to retain it and fail to produce functional protein. Unlike many mi-INTs that act as reversible molecular switches, this intron is irreversibly processed by premature cleavage and polyadenylation to generate a long noncoding RNA, PINC. Exogenous PINC alters endogenous PTEN protein levels and cellular proliferation, even in PTEN-mutant cells, indicating PTEN- dependent and independent functions.