The POU4F2/Brn-3b transcription factor is required for the hypertrophic response to angiotensin II in the heart.

Adult hearts respond to increased workload such as prolonged stress or injury, by undergoing hypertrophic growth. During this process, the early adaptive responses are important for maintaining cardiac output whereas at later stages, pathological responses such as cardiomyocyte apoptosis and fibrosis cause adverse remodelling, that can progress to heart failure. Yet the factors that control transition from adaptive responses to pathological remodelling in the heart are not well understood. Here we describe the POU4F2/Brn-3b transcription factor (TF) as a novel regulator of adaptive hypertrophic responses in adult hearts since Brn-3b mRNA and protein are increased in angiotensin-II (AngII) treated mouse hearts with concomitant hypertrophic changes [increased heart weight:body weight (HW:BW) ratio]. These effects occur specifically in cardiomyocytes because Brn-3b expression is increased in AngII-treated primary cultures of neonatal rat ventricular myocytes (NRVM) or foetal heart-derived H9c2 cells, which undergo characteristic sarcomeric re-organisation seen in hypertrophic myocytes and express hypertrophic markers, ANP/ßMHC. The Brn-3b promoter is activated by known hypertrophic signalling pathways e.g. p42/p44 mitogen-activated protein kinase (MAPK/ERK1/2) or calcineurin (via NFAT). Brn-3b target genes, e.g. cyclin D1, GLUT4 and Bax, are increased at different stages following AngII treatment, supporting distinct roles in cardiac responses to stress. Furthermore, hearts from male Brn-3b KO mutant mice display contractile dysfunction at baseline but also attenuated hypertrophic responses to AngII treatment. Hearts from AngII-treated male Brn-3b KO mice develop further contractile dysfunction linked to extensive fibrosis/remodelling. Moreover, known Brn-3b target genes, e.g. GLUT4, are reduced in AngII-treated Brn-3b KO hearts, suggesting that Brn-3b and its target genes are important in driving adaptive hypertrophic responses in stressed heart.

POU4F2/Brn-3b transcription factor is associated with survival and drug resistance in human ovarian cancer cells.

The development of drug resistance following treatment with chemotherapeutic agents such as cisplatin (cis) and paclitaxel (pax) contributes to high morbidity and mortality in ovarian cancers. However, the molecular mechanisms underlying such changes are not well understood. In this study, we demonstrate that the Brn-3b transcription factor was increased in different ovarian cancer cells including SKOV3 and A2780 following treatment with cis and pax. Furthermore, sustained increases in Brn-3b were associated with survival in drug resistant cells and correlated with elevated HSP27 expression. In contrast, targeting Brn-3b for reduction using short interfering RNA (siRNA) also resulted in attenuated HSP27 expression. Importantly, blocking Brn-3b expression with siRNA in SKOV3 cells was associated with reduced cell numbers at baseline but also increased cell death after further treatment, indicating sensitization of cells. Similar results were obtained in the metastatic IP1 cell line derived from ascites of mice bearing SKOV3 tumours. These findings suggest that increased Brn-3b may confer resistance to chemotherapeutic drugs in ovarian cancer cells by regulating key target genes such as HSP27 and that targeting Brn-3b may provide a novel mechanism for treatment of drug resistant ovarian cancers.