biostudies-literatureUnknownHe TNCI NIH HHSThe POU2F3-POU2AF2/3 (OCA-T1/2) transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we found that the POU2F3 molecular subtype of SCLC (SCLC-P) exhibits an exquisite dependence on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. SCLC-P cell lines were sensitive to nanomolar levels of a mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degrader when compared to other molecular subtypes of SCLC. POU2F3 and its cofactors were found to interact with components of the mSWI/SNF complex. The POU2F3 transcription factor complex was evicted from chromatin upon mSWI/SNF ATPase degradation, leading to attenuation of downstream oncogenic signaling in SCLC-P cells.bioRxiv : the preprint server for biology2024.01.22.576669https://www.ebi.ac.uk/biostudies/studies/S-EPMC10849552biostudies-literatureTargeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies.PMC10849552R35 CA231996P50 CA186786Young EChing-Yi Tien JSamajdar SHou SKim NSu FZheng HMiner SJMehra RWang XParolia AWu XSZheng YMahapatra SAbbineni CChinnaiyan AMEyunni SQiao YHe TXiao LMannan RCao XKlingbeil OVakoc CRRamachandra MfalseTargeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies.The POU2F3-POU2AF2/3 (OCA-T1/2) transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we found that the POU2F3 molecular subtype of SCLC (SCLC-P) exhibits an exquisite dependence on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. SCLC-P cell lines were sensitive to nanomolar levels of a mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degrader when compared to other molecular subtypes of SCLC. POU2F3 and its cofactors were found to interact with components of the mSWI/SNF complex. The POU2F3 transcription factor complex was evicted from chromatin upon mSWI/SNF ATPase degradation, leading to attenuation of downstream oncogenic signaling in SCLC-P cells.2024-01-01T00:00:00Z2024 May2026-04-08T15:32:08.322Z2025-04-19T21:08:20.639ZS-EPMC108495523832823810.1101/2024.01.22.576669