Inhibition of CAF-1 histone chaperone complex triggers cytosolic DNA and dsRNA sensing pathways and induces intrinsic immunity of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide but only a few drugs are approved by the Food and Drug Administration (FDA) for treatment of advanced HCC patients. Immune checkpoint inhibitors (ICIs) therapy has emerged as a new and effective treatment for HCC, yet only a quarter of HCC patients are responsive to ICIs treatment. Epigenetic deregulation plays a critical role in HCC initiation and progression whereas the contribution of histone chaperones and histone variants in liver carcinogenesis remains largely unexplored. Herein, we unraveled the function of the histone chaperone complex Chromatin assembly factor 1 (CAF-1) in HCC development. CAF-1 consists of chromatin assembly factor 1 subunit A (CHAF1A) and chromatin assembly factor 1 subunit B (CHAF1B) component to incorporate newly synthesized H3.1 histone into chromatin during DNA replication, which is essential for heterochromatin formation, gene repression, and genome integrity. Both subunits of CAF-1 complex are significantly upregulated in human and mouse HCC and are associated with poor prognosis of HCC patients. Knockout of CAF-1 remarkably suppressed HCC growth in both in vitro and in vivo models. Mechanistically, iii depletion of CAF-1 induced replicative stress and chromatin instability, which eventually led to cytoplasmic DNA leakage as micronuclei. Also, Chromatin immunoprecipitation sequencing (ChIP-Seq) analyses revealed a massive H3.3 histone variant replacement upon CAF-1 knockout. Enrichment of euchromatic H3.3 increased chromatin accessibility and activated the expression of endogenous retrovirus elements (ERVs), a phenomenon known as viral mimicry. Altogether, cytosolic micronuclei and ERVs are recognized as ectopic elements by the Stimulator of interferon genes (STING) and double-stranded RNA (dsRNA) viral sensing pathways, respectively. Also, ERVs elements are translated into peptides with predicted immunogenic functions. As a result, knockout of CAF-1 activated immunogenicity, inflammatory response, and anti-tumor immune surveillance, thereby significantly enhancing the anti-cancer effect of immune checkpoint therapy in HCC. Our findings suggest that CAF-1 is essential for HCC development and targeting CAF-1 may awaken the anti-cancer immune response and may work cooperatively with ICIs treatment in cancer therapy. All in all, this study will advance our understanding of the roles of the CAF-1 complex in cancer development and highlight the therapeutic potential of targeting the CAF-1 complex as a novel epigenetic therapy for cancer treatment.