TY - JOUR
T1 - Therapeutic targeting of BAP1/ASXL3 sub-complex in ASCL1-dependent small cell lung cancer
AU - Tsuboyama, Natsumi
AU - Wang, Ru
AU - Szczepanski, Aileen Patricia
AU - Chen, Huanhuan
AU - Zhao, Zibo
AU - Shi, Lei
AU - Wang, Lu
N1 - Funding Information:
We would like to thank Dr. Julien Sage for the kind gifts of mouse small cell lung cancer cell lines KP1 and KP3, Dr. Feng Zhang for the kind gifts of the Px330 and lentiCRISPR v2 vectors.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/4/8
Y1 - 2022/4/8
N2 - Small cell lung cancer (SCLC) is an aggressive disease, with patients diagnosed with either early-stage, limited stage, or extensive stage of SCLC tumor progression. Discovering and targeting the functional biomarkers for SCLC will be crucial in understanding the molecular basis underlying SCLC tumorigenesis to better assist in improving clinical treatment. Emerging studies have demonstrated that dysregulations in BAP1 histone H2A deubiquitinase complex are collectively associated with pathogenesis in human SCLC. Here, we investigated the function of the oncogenic BAP1/ASXL3/BRD4 epigenetic axis in SCLC by developing a next-generation BAP1 inhibitor, iBAP-II, and focusing on the epigenetic balance established between BAP1 and non-canonical PRC1 complexes in regulating SCLC-specific transcriptional programming. We further demonstrated that pharmacologic inhibition of BAP1’s catalytic activity disrupted BAP1/ASXL3/BRD4 epigenetic axis by inducing protein degradation of the ASXL3 scaffold protein, which bridges BRD4 and BAP1 at active enhancers. Furthermore, treatment of iBAP-II represses neuroendocrine lineage-specific ASCL1/MYCL/E2F signaling in SCLC cell lines, and dramatically inhibits SCLC cell viability and tumor growth in vivo. In summary, this study has provided mechanistic insight into the oncogenic function of BAP1 in SCLC and highlighted the potential of targeting BAP1’s activity as a novel SCLC therapy.
AB - Small cell lung cancer (SCLC) is an aggressive disease, with patients diagnosed with either early-stage, limited stage, or extensive stage of SCLC tumor progression. Discovering and targeting the functional biomarkers for SCLC will be crucial in understanding the molecular basis underlying SCLC tumorigenesis to better assist in improving clinical treatment. Emerging studies have demonstrated that dysregulations in BAP1 histone H2A deubiquitinase complex are collectively associated with pathogenesis in human SCLC. Here, we investigated the function of the oncogenic BAP1/ASXL3/BRD4 epigenetic axis in SCLC by developing a next-generation BAP1 inhibitor, iBAP-II, and focusing on the epigenetic balance established between BAP1 and non-canonical PRC1 complexes in regulating SCLC-specific transcriptional programming. We further demonstrated that pharmacologic inhibition of BAP1’s catalytic activity disrupted BAP1/ASXL3/BRD4 epigenetic axis by inducing protein degradation of the ASXL3 scaffold protein, which bridges BRD4 and BAP1 at active enhancers. Furthermore, treatment of iBAP-II represses neuroendocrine lineage-specific ASCL1/MYCL/E2F signaling in SCLC cell lines, and dramatically inhibits SCLC cell viability and tumor growth in vivo. In summary, this study has provided mechanistic insight into the oncogenic function of BAP1 in SCLC and highlighted the potential of targeting BAP1’s activity as a novel SCLC therapy.
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U2 - 10.1038/s41388-022-02240-x
DO - 10.1038/s41388-022-02240-x
M3 - Article
C2 - 35194152
AN - SCOPUS:85124952718
SN - 0950-9232
VL - 41
SP - 2152
EP - 2162
JO - Oncogene
JF - Oncogene
IS - 15
ER -
