C646 inhibits G2/M cell cycle-related proteins and potentiates anti-tumor effects in pancreatic cancer

Hiroaki Ono,Yoshiya Ishikawa,Daisuke Ban,Kosuke Ogawa,Yoshiki Murase,Atsushi Kudo,Shuichi Watanabe,Shinji Tanaka,Keiichi Akahoshi,Toshiro Ogura,Minoru Tanabe,Tomotaka Kato,Hiromichi Ito,Yoshimitsu Akiyama,Yutaro Nakamura

doi:10.1038/s41598-021-89530-8

Hiroaki Ono, Yoshiya Ishikawa + Show 13 more

Open Access

https://doi.org/10.1038/s41598-021-89530-8

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Abstract

The activity of histone acetyltransferases (HATs) plays a central role in an epigenetic modification in cooperation with HDACs (histone deacetyl transferases). It is likely that malfunction of this enzymatic machinery controlling epigenetic modification is relevant to carcinogenesis and tumor progression. However, in pancreatic cancer, the clinical relevance of HAT activity and histone acetylation has remained unclear. We identified that H3 acetylation was expressed in all pancreatic cancer patients, indicating that H3 acetylation may be essential in pancreatic cancer cells. We also found that the HAT inhibitor C646 augmented anti-tumor effects in vitro by inhibiting cell proliferation and cell cycle progression concomitantly with suppression of acetylated H3K9 and H3K27 expression. C646 or p300 and CBP (CREB-binding protein)-specific siRNA treatment inhibited the transcription of the G2/M cell cycle regulatory proteins cyclin B1 and CDK1 (cyclin-dependent kinase 1). C646 treatment also inhibited tumor growth in vivo in a xenograft mouse model. C646 could be an effective therapeutic agent for pancreatic cancer. The epigenetic status of pancreatic cancers based on their level of histone H3 acetylation may influence patient survival. Epigenetic stratification according to H3K27 acetylation could be useful for predicting disease prognosis as well as the therapeutic efficacy of C646 in pancreatic cancer.

Highlights

The activity of histone acetyltransferases (HATs) plays a central role in an epigenetic modification in cooperation with HDACs
In vitro experiments using the HAT inhibitor C646 was performed to evaluate any functional implications of histone H3 acetylation for pancreatic cancer proliferation
In Panc[1] cells, which have a lower expression of histone acetylation, it was slightly inhibited by 40 μM of C646 (Supplementary Figure S1A)

Summary

Introduction

The activity of histone acetyltransferases (HATs) plays a central role in an epigenetic modification in cooperation with HDACs (histone deacetyl transferases). In pancreatic cancer, the clinical relevance of HAT activity and histone acetylation has remained unclear. Epigenetic stratification according to H3K27 acetylation could be useful for predicting disease prognosis as well as the therapeutic efficacy of C646 in pancreatic cancer. In addition to these transcriptional subtypes, it has been established that epigenetic mechanisms contribute to tumor p rogression[6]. Epigenetic modification such as histone acetylation and histone deacetylation plays a central role in producing divergent gene structures influencing functional phenotypes. That an imbalance in the activation of these enzymes can contribute to malignant transformation and tumor progression[6,9]

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