The METTL3 RNA Methyltransferase Regulates Transcriptional Networks in Prostate Cancer.
The METTL3 RNA Methyltransferase Regulates Transcriptional Networks in Prostate Cancer.
复制标题
METTL3 RNA甲基转移酶调控前列腺癌的转录网络。
作者：
前列腺癌是由雄激素受体调节的转录驱动的，是癌症死亡的主要原因。出于这个原因，雄激素剥夺疗法通常用于治疗晚期前列腺癌。这些治疗通常在出现治疗耐药和疾病进展之前的短时间内有效，以去势耐药前列腺癌或神经内分泌样疾病。这项研究的目的是探讨针对表位转录组的新疗法是否可能抑制雄激素信号，从而代表前列腺癌治疗的一种新方法。前列腺癌(PCA)是癌症相关死亡的主要原因，由雄激素受体(AR)信号异常驱动。因此，雄激素剥夺疗法(ADT)通过阻止雄激素的生物合成或通过AR信号传导抑制(ARSI)来抑制雄激素诱导的PCa进展是常见的治疗方法。N6-甲基腺苷(M6A)的RNA修饰参与调节mRNA的表达、翻译和选择性剪接，并通过这些机制参与癌症的发生和发展。RNA-m6A受METTL3 RNA甲基转移酶复合体以及FTO和ALKBH5去甲基酶的动态调节。虽然有证据支持异常的METTL3在许多癌症类型中的作用，包括局限性的PCa，但METTL3的更广泛的贡献，以及由此推断的M6A，在PCa中的雄激素信号转导中仍然知之甚少。因此，本研究的目的是研究METTL3在PCa患者中的表达，并探讨其在PCa中的临床和功能相关性。研究发现，METTL3在PCa患者样本中异常表达，siRNA介导的METTL3基因敲除或METTL3药物抑制显著改变了PCa的基础转录组和雄激素调节的转录组，这支持了靶向M6A作为一种新的途径来调节PCa中的雄激素信号。
Prostate cancer is driven by androgen receptor-regulated transcription and is a leading cause of cancer deaths. For this reason, androgen deprivation therapies are commonly used to treat advanced prostate cancer. These treatments are often effective for short durations before the emergence of treatment resistance and disease progression to castrate resistant prostate cancer or neuroendocrine-like disease. The aim of this study was to address whether new therapies targeting the epitranscriptome may suppress androgen signalling and thus represent a novel approach to prostate cancer treatment. Prostate cancer (PCa) is a leading cause of cancer-related deaths and is driven by aberrant androgen receptor (AR) signalling. For this reason, androgen deprivation therapies (ADTs) that suppress androgen-induced PCa progression either by preventing androgen biosynthesis or via AR signalling inhibition (ARSi) are common treatments. The N6-methyladenosine (m6A) RNA modification is involved in regulating mRNA expression, translation, and alternative splicing, and through these mechanisms has been implicated in cancer development and progression. RNA-m6A is dynamically regulated by the METTL3 RNA methyltransferase complex and the FTO and ALKBH5 demethylases. While there is evidence supporting a role for aberrant METTL3 in many cancer types, including localised PCa, the wider contribution of METTL3, and by inference m6A, in androgen signalling in PCa remains poorly understood. Therefore, the aim of this study was to investigate the expression of METTL3 in PCa patients and study the clinical and functional relevance of METTL3 in PCa. It was found that METTL3 is aberrantly expressed in PCa patient samples and that siRNA-mediated METTL3 knockdown or METTL3-pharmacological inhibition significantly alters the basal and androgen-regulated transcriptome in PCa, which supports targeting m6A as a novel approach to modulate androgen signalling in PCa.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
82.9
作者：
Beltran H;Prandi D;Mosquera JM;Benelli M;Puca L;Cyrta J;Marotz C;Giannopoulou E;Chakravarthi BV;Varambally S;Tomlins SA;Nanus DM;Tagawa ST;Van Allen EM;Elemento O;Sboner A;Garraway LA;Rubin MA;Demichelis F
通讯作者：
Demichelis F
影响因子：
10.5
作者：
Ke S;Alemu EA;Mertens C;Gantman EC;Fak JJ;Mele A;Haripal B;Zucker-Scharff I;Moore MJ;Park CY;Vågbø CB;Kusśnierczyk A;Klungland A;Darnell JE Jr;Darnell RB
通讯作者：
Darnell RB
DOI：
10.1261/rna.065219.117
发表时间：
2018-03
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Darnell RB;Ke S;Darnell JE Jr
通讯作者：
Darnell JE Jr
影响因子：
6.6
作者：
Kashyap, Vasundhra;Ahmad, Shafqat;Nilsson, Emeli M.;Helczynski, Leszek;Kenna, Sinead;Persson, Jenny Liao;Gudas, Lorraine J.;Mongan, Nigel P.
通讯作者：
Mongan, Nigel P.