Mohammad Asad, Jha Sudhakar
Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA.
Cells. 2025 May 9;14(10):686. doi: 10.3390/cells14100686.
HIV-1 Tat-interactive protein of 60 kDa (TIP60) is a lysine acetyltransferase protein that can acetylate histone and non-histone proteins. This study highlights TIP60's role in regulating colorectal cancer (CRC) stemness. The depletion of resulted in a marked decrease in cellular proliferation, highlighting TIP60's involvement in the progression of CRC. Additionally, the loss of TIP60 impacted colony formation, transitioning from densely packed structures to dispersed spindle networks along with the loss of E-cadherin, indicating its role in the epithelial-mesenchymal transition (EMT). Three-dimensional culture models suggest that TIP60 is vital for spheroid formation, highlighting its importance in maintaining cancer stem cell properties in CRC. -depleted cells showed increased invasion in a 3D basement membrane extract (BME) invasion matrix, demonstrating its essential role in cellular invasiveness. Mechanistically, the reduction of TIP60 resulted in a decrease in expression, a critical marker for cancer stem cells (CSCs). Notably, overexpression restored the efficiency of spheroid formation and cell proliferation while reversing the EMT phenotype. Developing the TIP60-CD44 axis as a therapeutic target to treat CRC stemness and metastasis will help decrease the burden due to the deadly disease.
60 kDa的HIV-1反式激活因子相互作用蛋白（TIP60）是一种赖氨酸乙酰转移酶蛋白，可使组蛋白和非组蛋白乙酰化。本研究强调了TIP60在调节结直肠癌（CRC）干性中的作用。TIP60的缺失导致细胞增殖显著下降，突出了TIP60参与CRC的进展。此外，TIP60的缺失影响集落形成，随着E-钙黏蛋白的丧失，从紧密堆积的结构转变为分散的纺锤体网络，表明其在上皮-间质转化（EMT）中的作用。三维培养模型表明，TIP60对球体形成至关重要，突出了其在维持CRC中癌症干细胞特性方面的重要性。TIP60缺失的细胞在三维基底膜提取物（BME）侵袭基质中显示出侵袭增加，证明了其在细胞侵袭性中的重要作用。从机制上讲，TIP60的减少导致癌症干细胞（CSCs）的关键标志物表达下降。值得注意的是，过表达恢复了球体形成效率和细胞增殖，同时逆转了EMT表型。将TIP60-CD44轴开发为治疗CRC干性和转移的治疗靶点将有助于减轻这种致命疾病带来的负担。
