Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Clin Epigenetics. 2020 Jun 17;12(1):87. doi: 10.1186/s13148-020-00878-6.
Cancer subtype switching, which involves unclear cancer cell origin, cell fate decision, and transdifferentiation of cells within a confined tumor microenvironment, remains a major problem in pancreatic cancer (PDA).
By analyzing PDA subtypes in The Cancer Genome Atlas, we identified that epigenetic silencing of apoptosis-associated tyrosine kinase (AATK) inversely was correlated with mRNA expression and was enriched in the quasi-mesenchymal cancer subtype. By comparing early mouse pancreatic lesions, the non-invasive regions showed AATK co-expression in cells with acinar-to-ductal metaplasia, nuclear VAV1 localization, and cell cycle suppression; but the invasive lesions conversely revealed diminished AATK expression in those with poorly differentiated histology, cytosolic VAV1 localization, and co-expression of p63 and HNF1α. Transiently activated AATK initiates acinar differentiation into a ductal cell fate to establish apical-basal polarization in acinar-to-ductal metaplasia. Silenced AATK and ectopically expressed p63 and HNF1α allow the proliferation of ductal PanINs in mice.
Epigenetic silencing of AATK regulates the cellular transdifferentiation, proliferation, and cell cycle progression in converting PDA-subtypes.
癌症亚型转换涉及到不明确的癌细胞起源、细胞命运决定以及局限于肿瘤微环境中的细胞转分化，这仍然是胰腺癌（PDA）的一个主要问题。
通过分析癌症基因组图谱中的 PDA 亚型，我们发现凋亡相关酪氨酸激酶（AATK）的表观遗传沉默与 mRNA 表达呈负相关，并在准间质癌症亚型中富集。通过比较早期小鼠胰腺病变，非侵袭性区域显示出具有腺泡-导管化生的细胞中 AATK 的共表达、VAV1 核定位以及细胞周期抑制；但相反，侵袭性病变显示出那些具有低分化组织学、胞质 VAV1 定位以及 p63 和 HNF1α 共表达的细胞中 AATK 表达减少。瞬时激活的 AATK 启动了腺泡分化为导管细胞命运，在腺泡-导管化生中建立了顶端-基底极性。沉默的 AATK 和异位表达的 p63 和 HNF1α 允许小鼠中的导管 PanIN 增殖。
AATK 的表观遗传沉默调节了 PDA 亚型转化中细胞的转分化、增殖和细胞周期进程。
