Loss of KDM6A characterizes a poor prognostic subtype of human pancreatic cancer and potentiates HDAC inhibitor lethality

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.

Loss of ARID1A Promotes Epithelial–Mesenchymal Transition and Sensitizes Pancreatic Tumors to Proteotoxic Stress

“…In particular, we found that ARID1A-mutant cells are significantly more sensitive to NVP-AUY922 compared to Author Manuscript Published OnlineFirst on November 6, 2020; DOI: 10.1158/0008-5472. like KDM6A (33), though other unknown mechanisms may also be at play. Loss of ARID1A expression is typically induced by nonsense mutations, insertions, and deletions in the genecoding region, which lead to mRNA decay or sequence truncation (14).…”

KDM6A suppresses hepatocellular carcinoma cell proliferation by negatively regulating the TGF‑β/SMAD signaling pathway

“…Mechanistically, KDM6A mutations suppress cell proliferation by activating retinoblastoma protein-related genes, which suggests that KDM6A serves as a putative tumor suppressor (12). Furthermore, the biological function of KDM6A in a number of malignancies, including bladder and lung cancer, as well as pancreatic ductal adenocarcinoma, has been reported (13)(14)(15)(16). However, the cellular and molecular mechanisms underlying KDM6A in HCC are not completely understood.…”

Dramatic increase in gene mutational burden after transformation of follicular lymphoma into TdT+ B-lymphoblastic leukemia/lymphoma

“…KDM6A (also known as UTX) functions as a histone H3K27 demethylase, removing the repressive H3K27 methylation mark to foster transcriptional gene activation (van Haaften et al 2009). There is strong evidence that loss-of-function mutations in KDM6A, an established tumor-suppressor gene, play a role in cancer progression (Watanabe et al 2018). Sequencing efforts of both hematologic and nonhematologic malignancies in humans support this notion (van Haaften et al 2009;Van der Meulen et al 2015;Waddell et al 2015;Chakravarty et al 2017;Gozdecka et al 2018).…”