A p300/GATA6 axis determines differentiation and Wnt dependency in pancreatic cancer models.
A p300/GATA6 axis determines differentiation and Wnt dependency in pancreatic cancer models.
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DOI：
10.1172/jci156305
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发表时间：
2022-06-15
影响因子：
15.9
通讯作者：
Virshup, David M.
中科院分区：
文献类型：
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作者：
Zhong, Zheng;Harmston, Nathan;Wood, Kris C.;Madan, Babita;Virshup, David M.
Wnt信号调节多种组织和癌症中干细胞和分化之间的平衡。rnf43突变型胰腺癌依赖于Wnt的产生，通过药物阻断该通路，例如通过PORCN抑制剂，可导致肿瘤分化。然而，已观察到对这些抑制剂的原发性耐药。为了阐明潜在的机制，我们对PORCN抑制剂敏感的rnf43突变胰腺癌异种移植物进行了体内CRISPR筛选。正如预期的那样，Wnt通路中丢失导致耐药的基因被鉴定出来，包括APC、AXIN1和CTNNBIP1。出乎意料的是，筛选还发现了组蛋白乙酰转移酶EP300 (p300)，但没有发现其类似物CREBBP （CBP）。我们发现，由于所有现有的对PORCN抑制剂具有抗性的rnf43突变胰腺癌细胞系的遗传改变，EP300被沉默。从机制上讲，EP300的缺失直接下调了GATA6的表达，从而沉默了GATA6调控的分化程序，导致胰腺癌从经典亚型向去分化的基底样/鳞状亚型转变。EP300突变和GATA6功能的丧失绕过了Wnt信号的抗分化活性，使这些癌细胞对Wnt抑制产生抗性。
Wnt signaling regulates the balance between stemness and differentiation in multiple tissues and in cancer. RNF43-mutant pancreatic cancers are dependent on Wnt production, and pharmacologic blockade of the pathway, e.g., by PORCN inhibitors, leads to tumor differentiation. However, primary resistance to these inhibitors has been observed. To elucidate potential mechanisms, we performed in vivo CRISPR screens in PORCN inhibitor–sensitive RNF43-mutant pancreatic cancer xenografts. As expected, genes in the Wnt pathway whose loss conferred drug resistance were identified, including APC, AXIN1, and CTNNBIP1. Unexpectedly, the screen also identified the histone acetyltransferase EP300 (p300), but not its paralog, CREBBP (CBP). We found that EP300 is silenced due to genetic alterations in all the existing RNF43-mutant pancreatic cancer cell lines that are resistant to PORCN inhibitors. Mechanistically, loss of EP300 directly downregulated GATA6 expression, thereby silencing the GATA6-regulated differentiation program and leading to a phenotypic transition from the classical subtype to the dedifferentiated basal-like/squamous subtype of pancreatic cancer. EP300 mutation and loss of GATA6 function bypassed the antidifferentiation activity of Wnt signaling, rendering these cancer cells resistant to Wnt inhibition.