p53 mitigates the effects of oncogenic HRAS in urothelial cells via the repression of MCOLN1.
p53 mitigates the effects of oncogenic HRAS in urothelial cells via the repression of MCOLN1.
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DOI：
10.1016/j.isci.2021.102701
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发表时间：
2021-07-23
期刊：
影响因子：
5.8
通讯作者：
Venkatachalam K
中科院分区：
文献类型：
--
作者：
Jung J;Liao H;Coker SA;Liang H;Hancock JF;Denicourt C;Venkatachalam K
已知抑制由MCOLN 1编码的TRPML 1可阻止各种恶性肿瘤中的细胞增殖。在这里，我们报告说，肿瘤抑制因子，p53，抑制MCOLN 1在尿路上皮，无论是组成性损失或异位敲除TP 53-在健康和膀胱癌细胞增加MCOLN 1的表达。相反，nutlin介导的p53激活导致MCOLN 1的抑制。p53缺陷癌细胞中MCOLN 1表达升高，虽然不足以支持增殖，但增强了致癌HRAS对增殖、细胞因子产生和侵袭的影响。我们的数据表明，由于MCOLN 1的去抑制，缺乏p53的尿路上皮细胞准备由致癌HRAS驱动的肿瘤发生。鉴于我们先前的发现，即HRAS突变预测对TRPML 1的成瘾，本研究指出TRPML 1抑制剂可用于减轻缺乏p53的尿路上皮肿瘤亚组的生长。在缺乏p53的BLCA肿瘤中MCOLN 1表达升高p53在正常和转化的尿路上皮中抑制MCOLN 1在p53缺失后MCOLN 1诱导突变型HRAS的增强效应p53和HRAS突变的缺失预测膀胱癌中对TRPML 1的成瘾生物科学;分子生物学;细胞生物学;癌症
Inhibition of TRPML1, which is encoded by MCOLN1, is known to deter cell proliferation in various malignancies. Here, we report that the tumor suppressor, p53, represses MCOLN1 in the urothelium such that either the constitutive loss or ectopic knockdown of TP53—in both healthy and bladder cancer cells—increased MCOLN1 expression. Conversely, nutlin-mediated activation of p53 led to the repression of MCOLN1. Elevated MCOLN1 expression in p53-deficient cancer cells, though not sufficient for bolstering proliferation, augmented the effects of oncogenic HRAS on proliferation, cytokine production, and invasion. Our data suggest that owing to derepression of MCOLN1, urothelial cells lacking p53 are poised for tumorigenesis driven by oncogenic HRAS. Given our prior findings that HRAS mutations predict addiction to TRPML1, this study points to the utility of TRPML1 inhibitors for mitigating the growth of a subset of urothelial tumors that lack p53. MCOLN1 expression is elevated in BLCA tumors lacking p53 p53 represses MCOLN1 in both normal and transformed urothelium MCOLN1 induction upon p53 loss augmented effects of mutant HRAS Loss of p53 and HRAS mutations predict addiction to TRPML1 in bladder cancer Biological sciences; Molecular biology; Cell biology; Cancer
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