ACY-241, a histone deacetylase 6 inhibitor, suppresses the epithelial–mesenchymal transition in lung cancer cells by downregulating hypoxia-inducible factor-1 alpha

• 발행기관: 대한생리학회-대한약리학회
• 저자명: Seong-Jun Park Naeun Lee Chul-Ho Jeong
• 간행물 정보: 『The Korean Journal of Physiology & Pharmacology』제28권 제1호, 83~91쪽, 전체 9쪽
• 주제분류: 의약학 > 의학일반
• 파일형태: PDF
• 발행일자: 2024.01.31

국문 초록

Hypoxia-inducible factor-1 alpha (HIF-1α ) is a transcription factor acti - vated under hypoxic conditions, and it plays a crucial role in cellular stress regulation. While HIF-1 α activity is essential in normal tissues, its presence in the tumor microen - vironment represents a significant risk factor as it can induce angiogenesis and con - fer resistance to anti-cancer drugs, thereby contributing to poor prognoses. Typically, HIF-1 α undergoes rapid degradation in normoxic conditions via oxygen-dependent degradation mechanisms. However, certain cancer cells can express HIF-1 α even un - der normoxia. In this study, we observed an inclination toward increased normoxic HIF-1 α expression in cancer cell lines exhibiting increased HDAC6 expression, which prompted the hypothesis that HDAC6 may modulate HIF-1 α stability in normoxic conditions. To prove this hypothesis, several cancer cells with relatively higher HIF- 1 α levels under normoxic conditions were treated with ACY-241, a selective HDAC6 inhibitor, and small interfering RNAs for HDAC6 knockdown. Our data revealed a sig - nificant reduction in HIF-1 α expression upon HDAC6 inhibition. Moreover, the down - regulation of HIF-1 α under normoxic conditions decreased zinc finger E-box-binding homeobox 1 expression and increased E-cadherin levels in lung cancer H1975 cells, consequently suppressing cell invasion and migration. ACY-241 treatment also dem - onstrated an inhibitory effect on cell invasion and migration by reducing HIF-1 α level. This study confirms that HDAC6 knockdown and ACY-241 treatment effectively decrease HIF-1 α expression under normoxia, thereby suppressing the epithelial– mesenchymal transition. These findings highlight the potential of selective HDAC6 inhibition as an innovative therapeutic strategy for lung cancer

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키워드

ACY-241 (Citarinostat) Epithelial-mesenchymal transition Histone deacetylase 6 Hypoxia-inducible factor 1, alpha subunit