Hamila Sabryn A, Ooms Lisa M, Rodgers Samuel J, Mitchell Christina A
Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.
Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.
Adv Biol Regul. 2021 Dec;82:100817. doi: 10.1016/j.jbior.2021.100817. Epub 2021 Jun 16.
Cancer is a complex and heterogeneous disease marked by the dysregulation of cancer driver genes historically classified as oncogenes or tumour suppressors according to their ability to promote or inhibit tumour development and growth, respectively. Certain genes display both oncogenic and tumour suppressor functions depending on the biological context, and as such have been termed dual-role cancer driver genes. However, because of their context-dependent behaviour, the tumourigenic mechanism of many dual-role genes is elusive and remains a significant knowledge gap in our effort to understand and treat cancer. Inositol polyphosphate 4-phosphatase type II (INPP4B) is an emerging dual-role cancer driver gene, primarily known for its role as a negative regulator of the phosphoinositide 3-kinase (PI3K)/AKT signalling pathway. In response to growth factor stimulation, class I PI3K generates PtdIns(3,4,5)P at the plasma membrane. PtdIns(3,4,5)P can be hydrolysed by inositol polyphosphate 5-phosphatases to generate PtdIns(3,4)P, which, together with PtdIns(3,4,5)P, facilitates the activation of AKT to promote cell proliferation, survival, migration, and metabolism. Phosphatase and tensin homology on chromosome 10 (PTEN) and INPP4B are dual-specificity phosphatases that hydrolyse PtdIns(3,4,5)P and PtdIns(3,4)P, respectively, and thus negatively regulate PI3K/AKT signalling. PTEN is a bona fide tumour suppressor that is frequently lost in human tumours. INPP4B was initially characterised as a tumour suppressor akin to PTEN, and has been implicated as such in a number of cancers, including prostate, thyroid, and basal-like breast cancers. However, evidence has since emerged revealing INPP4B as a paradoxical oncogene in several malignancies, with increased INPP4B expression reported in AML, melanoma and colon cancers among others. Although the tumour suppressive function of INPP4B has been mostly ascribed to its ability to negatively regulate PI3K/AKT signalling, its oncogenic function remains less clear, with proposed mechanisms including promotion of PtdIns(3)P-dependent SGK3 signalling, inhibition of PTEN-dependent AKT activation, and enhancing DNA repair mechanisms to confer chemoresistance. Nevertheless, research is ongoing to identify the factors that dictate the tumourigenic output of INPP4B in different human cancers. In this review we discuss the dualistic role that INPP4B plays in the context of cancer development, progression and treatment, drawing comparisons to PTEN to explore how their similarities and, importantly, their differences may account for their diverging roles in tumourigenesis.
癌症是一种复杂的异质性疾病，其特征在于癌症驱动基因的失调，这些基因根据其促进或抑制肿瘤发展和生长的能力，历史上分别被归类为癌基因或肿瘤抑制基因。某些基因根据生物学背景同时具有致癌和肿瘤抑制功能，因此被称为双功能癌症驱动基因。然而，由于它们依赖于背景的行为，许多双功能基因的致瘤机制难以捉摸，并且在我们理解和治疗癌症的努力中仍然存在重大的知识空白。II型肌醇多磷酸4-磷酸酶（INPP4B）是一种新兴的双功能癌症驱动基因，主要因其作为磷酸肌醇3-激酶（PI3K）/AKT信号通路的负调节因子的作用而闻名。响应生长因子刺激，I类PI3K在质膜上产生磷脂酰肌醇-3,4,5-三磷酸（PtdIns(3,4,5)P）。PtdIns(3,4,5)P可被肌醇多磷酸5-磷酸酶水解生成磷脂酰肌醇-3,4-二磷酸（PtdIns(3,4)P），PtdIns(3,4)P与PtdIns(3,4,5)P一起促进AKT的激活，从而促进细胞增殖、存活、迁移和代谢。10号染色体上的磷酸酶和张力蛋白同源物（PTEN）和INPP4B是双特异性磷酸酶，分别水解PtdIns(3,4,5)P和PtdIns(3,4)P，从而负调节PI3K/AKT信号通路。PTEN是一种真正的肿瘤抑制因子，在人类肿瘤中经常缺失。INPP4B最初被表征为类似于PTEN 的肿瘤抑制因子，并在包括前列腺癌、甲状腺癌和基底样乳腺癌在内的多种癌症中被认为具有这种作用。然而，此后有证据表明INPP4B在几种恶性肿瘤中是一种矛盾的癌基因，在急性髓系白血病（AML）、黑色素瘤和结肠癌等癌症中报道了INPP4B表达增加。尽管INPP4B的肿瘤抑制功能主要归因于其负调节PI3K/AKT信号通路的能力，但其致癌功能仍不太清楚，提出的机制包括促进依赖磷脂酰肌醇-3-磷酸（PtdIns(3)P）的血清/糖皮质激素调节激酶3（SGK3）信号传导、抑制依赖PTEN的AKT激活以及增强DNA修复机制以赋予化学抗性。尽管如此，仍在进行研究以确定决定INPP4B在不同人类癌症中致瘤输出的因素。在这篇综述中，我们讨论了INPP4B在癌症发展、进展和治疗背景下所起的双重作用，并与PTEN进行比较，以探讨它们的异同，以及这些异同如何解释它们在肿瘤发生中不同的作用。
