NEAT1 repression by MED12 creates chemosensitivity in p53 wild‐type breast cancer cells

Breast cancer is often treated with chemotherapy. However, the development of chemoresistance results in treatment failure. Long non‐coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been shown to contribute to chemoresistance in breast cancer cells. In studying the transcriptional regulation of NEAT1 using multi‐omics approaches, we showed that NEAT1 is up‐regulated by 5‐fluorouracil in breast cancer cells with wild‐type cellular tumor antigen p53 but not in mutant‐p53‐expressing breast cancer cells. The regulation of NEAT1 involves mediator complex subunit 12 (MED12)‐mediated repression of histone acetylation marks at the promoter region of NEAT1. Knockdown of MED12 but not coactivator‐associated arginine methyltransferase 1 (CARM1) induced histone acetylation at the NEAT1 promoter, leading to elevated NEAT1 mRNAs, resulting in a chemoresistant phenotype. The MED12‐dependent regulation of NEAT1 differs between wild‐type and mutant p53‐expressing cells. MED12 depletion led to increased expression of NEAT1 in a wild‐type p53 cell line, but decreased expression in a mutant p53 cell line. Chemoresistance caused by MED12 depletion can be partially rescued by NEAT1 knockdown in p53 wild‐type cells. Collectively, our study reveals a novel mechanism of chemoresistance dependent on MED12 transcriptional regulation of NEAT1 in p53 wild‐type breast cancer cells. We found that NEAT1 is upregulated by chemotherapy in wild‐type p53‐expressing but not in mutant‐p53‐expressing breast cancer cells. The regulation of NEAT1 involves MED12‐mediated repression of histone acetylation marks at the promoter region of NEAT1. MED12 knockdown induced histone acetylation at the NEAT1 promoter, leading to elevated NEAT1 mRNA, resulting in a chemoresistant phenotype. Chemoresistance caused by MED12 depletion can be partially rescued by NEAT1 knockdown in p53 wild‐type cells.