Dauch Cara, Shim Sharon, Cole Matthew Wyatt, Pollock Nijole C, Beer Abigail J, Ramroop Johnny, Klee Victoria, Allain Dawn C, Shakya Reena, Knoblaugh Sue E, Kulewsky Jesse, Toland Amanda Ewart
Department of Cancer Biology and Genetics, The Ohio State University College of Medicine Columbus, OH 43210, USA.
Central Michigan University College of Medicine Mount Pleasant, MI 48858, USA.
Am J Cancer Res. 2022 Mar 15;12(3):1309-1322. eCollection 2022.
Cutaneous squamous cell carcinoma (cSCC) is the second most lethal skin cancer. Due to ultraviolet light-induced damage, cSCCs have a high mutation rate, but some genes are more frequently mutated in aggressive cSCCs. Lysine-specific histone methyltransferase 2D () has a two-fold higher mutation frequency in metastatic cSCCs relative to primary non-metastatic associated cSCCs. The role of KMT2D in more aggressive phenotypes in cSCC is uncharacterized. Studies of other tumor types suggest that KMT2D acts to suppress tumor development. To determine whether KMT2D loss has an impact on tumor characteristics, we disrupted in a cSCC cell line using CRISPR-cas9 and performed phenotypic analyses. KMT2D loss modestly increased cell proliferation and colony formation (1.4- and 1.6-fold respectively). Cells lacking KMT2D showed increased rates of migration and faster cell cycle progression. In xenograft models, tumors with KMT2D loss showed slight increases in mitotic indices. Collectively, these findings suggest that loss-of-function mutations may promote more aggressive and invasive behaviors in cSCC, suggesting that KMT2D-related pathways could be targets for cancer therapies. Future studies to determine the downstream genes and mechanism of phenotypic effect are needed.
皮肤鳞状细胞癌（cSCC）是第二大致命性皮肤癌。由于紫外线诱导的损伤，cSCC具有较高的突变率，但某些基因在侵袭性cSCC中更频繁地发生突变。赖氨酸特异性组蛋白甲基转移酶2D（KMT2D）在转移性cSCC中的突变频率相对于原发性非转移性相关cSCC高出两倍。KMT2D在cSCC更具侵袭性表型中的作用尚未明确。对其他肿瘤类型的研究表明，KMT2D起到抑制肿瘤发展的作用。为了确定KMT2D缺失是否对肿瘤特征有影响，我们使用CRISPR - cas9在一个cSCC细胞系中破坏KMT2D并进行了表型分析。KMT2D缺失适度增加了细胞增殖和集落形成（分别为1.4倍和1.6倍）。缺乏KMT2D的细胞显示出迁移率增加和细胞周期进展加快。在异种移植模型中，KMT2D缺失的肿瘤有丝分裂指数略有增加。总体而言，这些发现表明KMT2D功能丧失突变可能促进cSCC中更具侵袭性和浸润性的行为，这表明与KMT2D相关的途径可能是癌症治疗的靶点。需要进一步的研究来确定表型效应的下游基因和机制。
