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bioRxiv · 10.1101/2020.10.14.338590

HDAC3 regulates senescence and lineage-specific transcriptional programs in non-small cell lung cancer

Eichner, L. J.·Curtis, S. D.·Brun, S. N.·Baumgart, J. T.·Ross, D. S.·Rymoff, T. J.·Shaw, R. J.
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Abstract

Transcriptional deregulation is a common feature of many cancers, which is often accompanied by changes in epigenetic controls. These findings have led to the development of therapeutic agents aimed at broad modulation and reprogramming of transcription in a variety of cancers. Histone Deacetylase 3, HDAC3, is one of the main targets of HDAC inhibitors currently in clinical development as cancer therapies, yet the in vivo role of HDAC3 in solid tumors is unknown. Here, we define the role of HDAC3 in two genetic engineered models of the most common subtypes of Kras-driven Non-Small Cell Lung Cancer (NSCLC), KrasG12D, STK11-/- (KL) and KrasG12D, p53-/- (KP), where we found that HDAC3 is strongly required for tumor growth of both genotypes in vivo. Transcriptional profiling and mechanistic studies revealed that HDAC3 represses p65 NF-{kappa}B-mediated induction of the Senescence Associated Secretory Program (SASP) and HDAC3 binds directly at the promoters of SASP CXC chemokines. Additionally, HDAC3 was found to cooperate with the lung cancer lineage transcription factor NKX2-1 to mediate expression of a common set of target genes. Leveraging observations about one HDAC3/NKX2-1 common target, FGFR1, we identified that an HDAC3-dependent transcriptional cassette becomes hyperactivated as Kras mutant cancer cells develop resistance to the MEK inhibitor Trametinib, and this can be rescued by treatment with the Class I HDAC inhibitor Entinostat. These unexpected findings reveal new roles for HDAC3 in proliferation control in tumors in vivo and identify specific therapeutic contexts for the utilization of HDAC3 inhibitors, whose ability to mechanistically induce SASP may be harnessed therapeutically.

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Eichner, L. J., Curtis, S. D., Brun, S. N., Baumgart, J. T., Ross, D. S., Rymoff, T. J., Shaw, R. J.. 2020-10-14. HDAC3 regulates senescence and lineage-specific transcriptional programs in non-small cell lung cancer. https://doi.org/10.1101/2020.10.14.338590

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