SETD2 and miR-21 as therapeutic targets for NUT midline carcinoma （NUT midline carcinomaの新規治療におけるSETD2とmiR-21の検討）
著者
吉田, 奈七
(Yoshida, Nana)
上位タイトル
Journal of Cancer Science and Clinical Therapeutics
Vol.6,
No.1
(2022.
3)
,p.129-
135
識別番号
ISSN
2637-5079
博士論文情報
学位授与番号
10107A587
学位授与年月日
2023-3-24
学位名
博士（医学）
学位授与機関
旭川医科大学
抄録
Nuclear Protein in Testis (NUT) Midline Carcinoma (NMC) is a rare and highly aggressive tumor with the bromodomain containing 4 proteins (BRD4)-NUT (NUTM1) gene fusion. Few targeted therapies are available for NMC, and thus novel therapeutic targets are required. To the best of our knowledge, the present study was the first to report that SET domain-containing protein 2 (SETD2) deficiency and microRNA (miRNA/miR)-21 may serve as novel therapeutic targets for the treatment of NMC. First, Next-Generation Sequencing (NGS) identified a novel SETD2 mutation (p.Ser2382fs) in the NMC cell lines, HCC2429 and Ty82. Trimethylation of lysine 36 on histone H3 expression was depleted in the NMC cells, which was indicative of SETD2 loss. NMC cells were sensitive to the WEE1 G2 checkpoint kinase (WEE1) inhibitor, AZD1775, in the cancer cells with SETD2 deficiency. NMC cells that were resistant to Bromodomain and Extra-Terminal Motif (BET) inhibitors were next established, and these resistant cells were also sensitive to AZD1775. Subsequently, miRNA analysis revealed that miR-21 expression was increased in BET-inhibitor-resistant NMC cells. In addition, miR-21 regulated the proliferation of NMCs. The miR-21 inhibitor also suppressed the proliferation of BET-inhibitor-resistant cells. Additionally, a digital PCR assay was established to detect NUT gene rearrangements to identify patients with NMC. A total of 32 clinical samples were analyzed and one case of NMC was identified, in which the novel SETD2 mutation was detected. These data suggested that SETD2 loss and miR-21 may be therapeutic targets for treatment of NMC.
