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

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

doi:10.1097/HEP.0000000000000709

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

Hepatology. 2023 Dec 5. doi: 10.1097/HEP.0000000000000709. Online ahead of print.

Authors

For-Fan Chan¹, Vincent Wai-Hin Yuen^{1

2}, Jialing Shen¹, Don Wai-Ching Chin¹, Cheuk-Ting Law¹, Bowie Po-Yee Wong^{1

2}, Cerise Yuen-Ki Chan^{1

2}, Jacinth Wing-Sum Cheu^{1

2}, Irene Oi-Lin Ng¹, Carmen Chak-Lui Wong^{1

2}, Chun-Ming Wong¹

Affiliations

¹ State Key Laboratory of Liver Research, Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
² Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China.

PMID: 38051950
DOI: 10.1097/HEP.0000000000000709

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.