Combined Kdm6a and Trp53 Deficiency Drives the Development of Squamous Cell Skin Cancer in Mice.
Combined Kdm6a and Trp53 Deficiency Drives the Development of Squamous Cell Skin Cancer in Mice.
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Kdm6a 和 Trp53 联合缺乏会导致小鼠鳞状细胞皮肤癌的发生。
DOI：
10.1016/j.jid.2022.08.037
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Chen,DavidY
中科院分区：
文献类型：
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作者：
Shea,LaurenK;Akhave,NealS;Sutton,LeslieA;Compton,LeighA;York,Conner;Ramakrishnan,SaiMukund;Miller,ChristopherA;Wartman,LukasD;Chen,DavidY
皮肤鳞状细胞癌(CSCC)是所有癌症中突变负担最高的肿瘤之一，反映了其致病机制与紫外线照射的诱变效应有关。虽然与癌症相关的基因突变，如TP53和NOTCH1在CSCC中很常见，但它们在正常皮肤中也是耐受的，这表明转化需要其他事件；尚不清楚表观遗传调节因子是否在CSCC的发病机制中起作用；KDM6A编码一种组蛋白H3K27me2/ME3去甲基酶，在CSCC和其他癌症中经常发生突变。先前的测序研究表明，大约7%的CSCC样本携带KDM6A突变，包括频繁的截断突变，这表明该基因在CSCC中作为肿瘤抑制因子发挥作用。Kdm6a和Trp53两种表皮缺陷的小鼠在一年内表现出100%穿透性的自发CSCC发展，由此产生的肿瘤的外显子组测序显示NcstnAnd和Vcan反复突变。在16个肿瘤中，有4个肿瘤在涉及Ncstn的1号染色体的大部分区域有缺失，而另外25%的肿瘤在涉及Pten的19号染色体上存在缺失，这意味着在依赖KDM6A和Trp53的联合肿瘤发生中，其他抑癌基因的缺失是协同事件。本研究提示KDM6A在CSCC的发病机制中起着重要的肿瘤抑制作用。
Cutaneous squamous cell carcinoma (cSCC) has among the highest mutation burdens of all cancers, reflecting its pathogenic association with the mutagenic effects of UV light exposure. Although mutations in cancer-relevant genes such asTP53andNOTCH1are common in cSCC, they are also tolerated in normal skin and suggest that other events are required for transformation; it is not yet clear whether epigenetic regulators cooperate in the pathogenesis of cSCC.KDM6Aencodes a histone H3K27me2/me3 demethylase that is frequently mutated in cSCC and other cancers. Previous sequencing studies indicate that roughly 7% of cSCC samples harborKDM6Amutations, including frequent truncating mutations, suggesting a role for this gene as a tumor suppressor in cSCC. Mice with epidermal deficiency of bothKdm6aandTrp53exhibited 100% penetrant, spontaneous cSCC development within a year, and exome sequencing of resulting tumors reveals recurrent mutations inNcstnandVcan. Four of 16 tumors exhibited deletions in large portions of chromosome 1 involvingNcstn, whereas another 25% of tumors harbored deletions in chromosome 19 involvingPten, implicating the loss of other tumor suppressors as cooperating events for combined KDM6A- and TRP53-dependent tumorigenesis. This study suggests thatKDM6Aacts as an important tumor suppressor for cSCC pathogenesis.