Department of Biology, University of York, Heslington, York YO10 5DD, UK.
Université de Bordeaux, ARNA Laboratory, F-33076 Bordeaux, France INSERM, U1212 - CNRS UMR 5320, ARNA Laboratory, F-33000 Bordeaux, France.
Nucleic Acids Res. 2019 May 7;47(8):3937-3956. doi: 10.1093/nar/gkz128.
RNA polymerase (pol) III occurs in two forms, containing either the POLR3G subunit or the related paralogue POLR3GL. Whereas POLR3GL is ubiquitous, POLR3G is enriched in undifferentiated cells. Depletion of POLR3G selectively triggers proliferative arrest and differentiation of prostate cancer cells, responses not elicited when POLR3GL is depleted. A small molecule pol III inhibitor can cause POLR3G depletion, induce similar differentiation and suppress proliferation and viability of cancer cells. This response involves control of the fate-determining factor NANOG by small RNAs derived from Alu short interspersed nuclear elements. Tumour initiating activity in vivo can be reduced by transient exposure to the pol III inhibitor. Untransformed prostate cells appear less sensitive than cancer cells to pol III depletion or inhibition, raising the possibility of a therapeutic window.
RNA 聚合酶 (pol) III 有两种形式，分别含有 POLR3G 亚基或相关的同源 PARALOG POLR3GL。虽然 POLR3GL 是普遍存在的，但 POLR3G 在未分化细胞中富集。POLR3G 的耗竭选择性地触发前列腺癌细胞的增殖停滞和分化，而 POLR3GL 的耗竭则不会引起这些反应。一种小分子 pol III 抑制剂可以导致 POLR3G 的耗竭，诱导类似的分化并抑制癌细胞的增殖和活力。这种反应涉及到由 Alu 短散布核元件衍生的小 RNA 对命运决定因子 NANOG 的控制。体内肿瘤起始活性可以通过短暂暴露于 pol III 抑制剂来降低。未转化的前列腺细胞似乎比癌细胞对 pol III 耗竭或抑制的敏感性更低，这增加了治疗窗口的可能性。
