The POU-Domain Transcription Factor Oct-6/POU3F1 as a Regulator of Cellular Response to Genotoxic Stress

Abstract

DNA damage and the generation of reactive oxygen species (ROS) are key mechanisms of apoptotic cell death by commonly used genotoxic drugs. However, the complex cellular response to these pharmacologic agents remains yet to be fully characterized. Several studies have described the role of transcription factor octamer-1 (Oct-1)/Pit-1, Oct-1/2, and Unc-86 shared domain class 2 homeobox 1 (POU2F1) in the regulation of the genes important for cellular response to genotoxic stress. Evaluating the possible involvement of other POU family transcription factors in these pathways, we revealed the inducible expression of Oct-6/POU3F1, a regulator of neural morphogenesis and epidermal differentiation, in cancer cells by genotoxic drugs. The induction of Oct-6 occurs at the transcriptional level via reactive oxygen species (ROS) and ataxia telangiectasia mutated- and Rad3-related (ATR)-dependent mechanisms, but in a p53 independent manner. Moreover, we provide evidence that Oct-6 may play a role in the regulation of cellular response to DNA damaging agents. Indeed, by using the shRNA approach, we demonstrate that in doxorubicin-treated H460 non-small-cell lung carcinoma (NSCLC) cells, Oct-6 depletion leads to a reduced G2-cell cycle arrest and senescence, but also to increased levels of intracellular ROS and DNA damage. In addition, we could identify p21 and catalase as Oct-6 target genes possibly mediating these effects. These results demonstrate that Oct-6 is expressed in cancer cells after genotoxic stress, and suggests its possible role in the control of ROS, DNA damage response (DDR), and senescence.

Pou3f1 mediates the effect of Nfatc3 on ulcerative colitis-associated colorectal cancer by regulating inflammation

“…The regulation on TUNEL-positive cells seems important in the control of tumor progression of UC-CRC [ 36 ]. In line with previous studies, we demonstrated that Pou3f1 inhibition reduced pro-oncogenic cytokine production, suppressed cell proliferation and increased cell death in UC-CRC [ 22 , 37 ].…”

“…However, there is an inconsistency between ours and the previous results. Fionda et al indicated that Pou3f1 depletion increased the intracellular ROS levels in non-small-cell lung carcinoma cells in the presence of doxorubicin [ 22 ]. A possible reason for this discrepancy is that macrophages and cancer cells are heterogeneous.…”

“…Pou3f1 (also named as Oct-6, SCIP or Tst-1) is a member of the Pit-Oct-Unc (POU) family, and it regulates embryogenesis, epidermal differentiation and neurogenesis [18][19][20][21]. Fionda et al found that inhibition of Pou3f1 combined with doxorubicin induced G2-cell cycle arrest and cell apoptosis in non-small-cell lung carcinoma [22]. Hofmann et al demonstrated that Pou3f1 expression was increased in fibroblasts and macrophages in the presence of IFN-β and IFN-γ [23], implying its potential in regulating immune responses.…”

The POU2F1-ALDOA axis promotes the proliferation and chemoresistance of colon cancer cells by enhancing glycolysis and the pentose phosphate pathway activity

“…Previous studies have shown that transcription factors in the POU domain family are critical for cancer initiation and progression [ 21 , 22 ]. For example, OCT4 is important for stemness of cancer stem cells [ 23 ] and POU2F1 expression is up-regulated in head and neck squamous carcinoma [ 24 , 25 ].…”

Research progress of the transcription factor Brn4 (Review)

“…The POU3 family contains four members, Tst-1 [also known as POU domain, class 3, transcription factor 1 (POU3F1), Oct6, Test1, and SCIP], Brn1 (also known as POU3F3 and Oct8), Brn2 (also known as POU3F2 and Oct7) and Brn4 (also known as POU3F4, Oct9, deafness 3 and deafness X-linked 2). Tst-1 was originally identified in rat testes and glial cells, as well as in the developing brain and skin (5), and it is an important regulator of neurogenesis and epidermal differentiation (6). It has a dual regulatory function, not only does it activate neural lineage genes (such as Sox2), but it also represses neural-inhibitory signals (such as Wnt and bone morphogenetic protein), thus inhibiting cell proliferation (7,8).…”