1. Academic Validation
  2. Blockade of GRP78 Translocation to the Cell Surface by HDAC6 Inhibition Suppresses Proliferation of Cholangiocarcinoma Cells

Blockade of GRP78 Translocation to the Cell Surface by HDAC6 Inhibition Suppresses Proliferation of Cholangiocarcinoma Cells

  • Anticancer Res. 2022 Jan;42(1):471-482. doi: 10.21873/anticanres.15505.
Chorong Kim 1 Seonmin Lee 1 Danbee Kim 1 DA Sol Lee 1 Eunjung Lee 1 Changhoon Yoo 2 Kyu-Pyo Kim 3
Affiliations

Affiliations

  • 1 Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
  • 2 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
  • 3 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea kkp1122@amc.seoul.kr.
Abstract

Background/aim: HDAC6, a cytoplasmic localized deacetylase, is a positive regulator of Cancer progression via modification of various substrates. We evaluated how the interaction between HDAC6 and glucose regulatory protein 78 (GRP78) affects the growth of cholangiocarcinoma (CCA).

Materials and methods: The anti-tumor effects of ACY-1215, an HDAC6 specific inhibitor, in CCA cell lines were analyzed by cell viability assay, western blotting, flow cytometry, co-immunoprecipitation, and biotinylation assays. In vivo effects of ACY-1215 were evaluated in a xenograft model using CCA cell line TFK-1.

Results: ACY-1215 increased the acetyl-form of GRP78 by approximately 50% compared to control, which impaired the translocation of GRP78 to the plasma membrane by 50% through alteration of cellular proliferative signaling via PI3K/Akt. Furthermore, ACY-1215 suppressed tumor growth by 50% compared to vehicle control in a CCA xenograft model.

Conclusion: Increase in GRP78 acetylation by HDAC6 inhibition suppressed GRP78 translocation to the cell surface, which inhibited proliferation and promoted Apoptosis in CCA.

Keywords

ACY-1215; GRP78; HDAC6; acetylation; cholangiocarcinoma.

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