Drumond-Bock Ana Luiza, Wang Luyao, Wang Lin, Cybula Magdalena, Rostworowska Maria, Kinter Michael, Bieniasz Magdalena
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Cytovance Biologics, Oklahoma City, OK 73104, USA.
Genes Cancer. 2023 Sep 12;14:56-76. doi: 10.18632/genesandcancer.233. eCollection 2023.
Chemoresistance in ovarian carcinoma is a puzzling issue that urges understanding of strategies used by cancer cells to survive DNA damage and to escape cell death. Expanding efforts to understand mechanisms driving chemoresistance and to develop alternative therapies targeting chemoresistant tumors are critical. Amplification of is frequently associated with chemoresistant ovarian carcinoma, but little is known about the biological effects of the overexpression of BRD4 isoforms in this malignancy. Here, we described the consequences of BRD4-L and BRD4-S overexpression in ovarian carcinoma shedding a light on a complex regulation of BRD4 isoforms. We demonstrated that the BRD4-L transcript expression is required to generate both isoforms, BRD4-L and BRD4-S. We showed that the BRD4-S mRNA expression positively correlated with BRD4-S protein levels, while BRD4-L isoform showed negative correlation between mRNA and protein levels. Moreover, we demonstrated that an overexpression of BRD4 isoforms is associated with chemoresistance in ovarian cancer.
卵巢癌中的化疗耐药是一个令人困惑的问题，促使人们去了解癌细胞用于在DNA损伤中存活并逃避细胞死亡的策略。加大对驱动化疗耐药机制的理解力度以及开发针对化疗耐药肿瘤的替代疗法至关重要。BRD4的扩增常与化疗耐药的卵巢癌相关，但对于BRD4异构体在这种恶性肿瘤中过表达的生物学效应知之甚少。在此，我们描述了BRD4-L和BRD4-S在卵巢癌中过表达的后果，揭示了BRD4异构体的复杂调控。我们证明BRD4-L转录本表达是产生BRD4-L和BRD4-S这两种异构体所必需的。我们表明BRD4-S mRNA表达与BRD4-S蛋白水平呈正相关，而BRD4-L异构体在mRNA和蛋白水平之间呈负相关。此外，我们证明BRD4异构体的过表达与卵巢癌的化疗耐药相关。
