Brun, S. N. | bioRxiv Science

bioRxiv2020

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

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.

cancer biology↗

bioRxiv2020

Inhibition of CAMKK2 impairs autophagy and castration-resistant prostate cancer via suppression of AMPK-ULK1 signaling

Previous work has suggested androgen receptor (AR) signaling mediates cancer progression in part through the modulation of autophagy. Accordingly, we demonstrate that chloroquine, an inhibitor of autophagy, can inhibit tumor growth in preclinical mouse models of castration-resistant prostate cancer (CRPC). However, clinical trials testing chloroquine derivatives in men with CRPC have yet to yield promising results, potentially due to side effects. We hypothesized that identification of the upstream activators of autophagy in prostate cancer could highlight alternative, context-dependent targets for blocking this important cellular process during disease progression. Here, we used molecular (inducible overexpression and shRNA-mediated knockdown), genetic (CRISPR/Cas9), and pharmacological approaches to elucidate an AR-mediated autophagy cascade involving Ca2+/calmodulin-dependent protein kinase kinase 2 (CAMKK2; a kinase with a restricted expression profile), 5-AMP-activated protein kinase (AMPK) and Unc-51 like autophagy activating kinase 1 (ULK1). These findings are consistent with data indicating CAMKK2-AMPK-ULK1 signaling correlates with disease progression in genetic mouse models and patient tumor samples. Importantly, CAMKK2 disruption impaired tumor growth and prolonged survival in multiple CRPC preclinical mouse models. Finally, we demonstrate that, similar to CAMKK2 inhibition, a recently described inhibitor of AMPK-ULK1 signaling blocked autophagy, cell growth and colony formation in prostate cancer cells. Taken together, our findings converge to demonstrate that AR signaling can co-opt the CAMKK2-AMPK-ULK1 signaling cascade to promote prostate cancer by increasing autophagy. Further, we propose that an inhibitor of this signaling cascade could serve as an alternative, more specific therapeutic compared to existing inhibitors of autophagy that, to date, have demonstrated limited efficacy in clinical trials due to their toxicity and poor pharmacokinetics.

cancer biology↗