Wu Qiong, Sharma Soni, Cui Hang, LeBlanc Scott E, Zhang Hong, Muthuswami Rohini, Nickerson Jeffrey A, Imbalzano Anthony N
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA.
School of Life Sciences, Jawaharlal Nehru University, New Delhi, Delhi, India.
Oncotarget. 2016 May 10;7(19):27158-75. doi: 10.18632/oncotarget.8384.
Brahma related gene product 1 (BRG1) is an ATPase that drives the catalytic activity of a subset of the mammalian SWI/SNF chromatin remodeling enzymes. BRG1 is overexpressed in most human breast cancer tumors without evidence of mutation and is required for breast cancer cell proliferation. We demonstrate that knockdown of BRG1 sensitized triple negative breast cancer cells to chemotherapeutic drugs used to treat breast cancer. An inhibitor of the BRG1 bromodomain had no effect on breast cancer cell viability, but an inhibitory molecule that targets the BRG1 ATPase activity recapitulated the increased drug efficacy observed in the presence of BRG1 knockdown. We further demonstrate that inhibition of BRG1 ATPase activity blocks the induction of ABC transporter genes by these chemotherapeutic drugs and that BRG1 binds to ABC transporter gene promoters. This inhibition increased intracellular concentrations of the drugs, providing a likely mechanism for the increased chemosensitivity. Since ABC transporters and their induction by chemotherapy drugs are a major cause of chemoresistance and treatment failure, these results support the idea that targeting the enzymatic activity of BRG1 would be an effective adjuvant therapy for breast cancer.
与布拉马相关的基因产物1（BRG1）是一种ATP酶，可驱动哺乳动物SWI/SNF染色质重塑酶亚群的催化活性。BRG1在大多数人类乳腺癌肿瘤中过度表达且无突变迹象，并且是乳腺癌细胞增殖所必需的。我们证明，敲低BRG1可使三阴性乳腺癌细胞对用于治疗乳腺癌的化疗药物敏感。BRG1溴结构域的抑制剂对乳腺癌细胞活力没有影响，但靶向BRG1 ATP酶活性的抑制分子重现了在敲低BRG1时观察到的药物疗效增加。我们进一步证明，抑制BRG1 ATP酶活性可阻断这些化疗药物对ABC转运蛋白基因的诱导，并且BRG1与ABC转运蛋白基因启动子结合。这种抑制增加了药物的细胞内浓度，为化学敏感性增加提供了一种可能的机制。由于ABC转运蛋白及其被化疗药物诱导是化疗耐药和治疗失败的主要原因，这些结果支持了靶向BRG1的酶活性将是乳腺癌有效辅助治疗的观点。
