Loss of KDM6A characterizes a poor prognostic subtype of human pancreatic cancer and potentiates HDAC inhibitor lethality. Issue 1 (30th December 2018)

• Record Type: Journal Article
• Authors: Watanabe, Shuichi; Shimada, Shu; Akiyama, Yoshimitsu; Ishikawa, Yoshiya; Ogura, Toshiro; Ogawa, Kosuke; Ono, Hiroaki; Mitsunori, Yusuke; Ban, Daisuke; Kudo, Atsushi; Yamaoka, Shoji; Tanabe, Minoru; Tanaka, Shinji
• Is Part Of: International journal of cancer. Volume 145:Issue 1(2019)
• Page Start: 192
• Page End: 205
• Publication Date: 2018-12-30
• Subjects: pancreatic cancer -- KDM6A -- CDKN1A -- histone deacetylase inhibitor; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32072
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Although genomic analysis have recently discovered the malignant subtype of human pancreatic ductal adenocarcinoma (PDAC) characterized by frequent mutations of histone demethylase KDM6A, the biological and molecular roles still remain obscure. We herein elucidated the clinical and biological impacts of KDM6A deficiency on human PDAC and identified the therapeutic potential by pathological and molecular evaluation. Immunohistochemical analysis suggested that loss of KDM6A in cancerous tissues was an independent prognostic factor for both recurrence‐free and overall survival in the 103 tumor specimens surgically resected from patients with PDAC. We established KDM6A knocked out cells by using the CRISPR/Cas9 system and KDM6A‐expressed cells by doxycycline‐inducible system from each two human PDAC cell lines, respectively. KDM6A knockout enhanced aggressive traits of human PDAC cell lines, whereas KDM6A overexpression suppressed them. Microarray analysis revealed reduced expression of 22 genes including five well‐known tumor suppressors, such as CDKN1A, and ChIP‐PCR analysis displayed depleted enrichment of histone H3 lysine 27 acetylation (H3K27ac) at the promoter regions of the five candidates. The epigenetic alterations were induced by the impaired recruitment of histone acetyltransferase p300, which cooperatively interacted with KDM6A. Consistent with these results, the KDM6A knockout cells demonstrated higher vulnerability to histone deacetylase (HDAC) inhibitors through the reactivation of CDKN1A in vitro and in vivo than the KDM6A wild‐type. In conclusion, KDM6A exhibited essential roles in human PDAC as a tumor suppressor and KDM6A deficiency could be a promising biomarker for unfavorable outcome in PDAC patients and a potential surrogate marker for response to HDAC inhibitors. Abstract : What's new? Inactivating mutations in histone lysine demethylase gene KDM6A occur in various tumors, including human pancreatic ductal adenocarcinoma (PDAC). Little is known, however, about the role of KDM6A protein in PDAC. Here, KDM6A knockout in human PDAC cells was found to enhance aggressive characteristics, including mitogenic capacity and invasiveness. KDM6A overexpression downregulated these effects, suggesting a tumor suppressor function for KDM6A. Additionally, H3K27 acetylation levels were downregulated in the promoter regions of tumor suppressor genes including CDKN1A in KDM6A‐deficient PDAC, and KDM6A knockout Cells exhibited increased vulnerability to histone deacetylase inhibitors, highlighting the potential of specific therapeutics in PDAC subtypes with poor prognosis.