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. 2024 Aug 1;80(2):295-311.
doi: 10.1097/HEP.0000000000000709. Epub 2023 Dec 5.

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

For-Fan Chan  1 , Vincent Wai-Hin Yuen  1   2 , Jialing Shen  1 , Don Wai-Ching Chin  1 , Cheuk-Ting Law  1 , Bowie Po-Yee Wong  1   2 , Cerise Yuen-Ki Chan  1   2 , Jacinth Wing-Sum Cheu  1   2 , Irene Oi-Lin Ng  1 , Carmen Chak-Lui Wong  1   2 , Chun-Ming Wong  1
Affiliations

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

For-Fan Chan et al. Hepatology. .

Abstract

Background and aims: Chromatin assembly factor 1 (CAF-1) is a replication-dependent epigenetic regulator that controls cell cycle progression and chromatin dynamics. In this study, we aim to investigate the immunomodulatory role and therapeutic potential of the CAF-1 complex in HCC.

Approach and results: CAF-1 complex knockout cell lines were established using the CRISPR/Cas9 system. The effects of CAF-1 in HCC were studied in HCC cell lines, nude mice, and immunocompetent mice. RNA-sequencing, ChIP-Seq, and assay for transposase accessible chromatin with high-throughput sequencing (ATAC-Seq) were used to explore the changes in the epigenome and transcriptome. CAF-1 complex was significantly upregulated in human and mouse HCCs and was associated with poor prognosis in patients with HCC. Knockout of CAF-1 remarkably suppressed HCC growth in both in vitro and in vivo models. Mechanistically, depletion of CAF-1 induced replicative stress and chromatin instability, which eventually led to cytoplasmic DNA leakage as micronuclei. Also, chromatin immunoprecipitation sequencing 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, a phenomenon known as viral mimicry. However, cytosolic micronuclei and endogenous retroviruses are recognized as ectopic elements by the stimulator of interferon genes and dsRNA viral sensing pathways, respectively. As a result, the knockout of CAF-1 activated inflammatory response and antitumor immune surveillance and thereby significantly enhanced the anticancer effect of immune checkpoint inhibitors in HCC.

Conclusions: Our findings suggest that CAF-1 is essential for HCC development; targeting CAF-1 may awaken the anticancer immune response and may work cooperatively with immune checkpoint inhibitor treatment in cancer therapy.

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