The deep sea is one of the most mysterious and unexplored extreme environments in the world, characterized by lack of light, low temperatures, anaerobic conditions, and hydrostatic pressures that could reach more than 1000 atmospheres (Thornburg et al., 2010). Over the past 50 years, there have been about 24,000 natural products of marine origin, but less than 2% of them come from deep-sea sources. Generally, deep-sea microorganisms have unique physiological metabolic processes by the adaptation to extreme environmental conditions, and thus exhibit the chemical structure diversity, novelty, and significant biological activity of their metabolites, such as anticancer (Skropeta and Wei, 2014). It has been reported that over 75% of natural products from deep-sea sources are bioactive, and more than half show significant cytotoxic activity against human tumor cell lines (Skropeta, 2008). As an important group of deep-sea microorganisms, deep-sea fungi are well known for their diversity of secondary metabolites, which have the potential to treat cancers and find new biological targets, providing important support for anticancer drug research and development (Xu et al., 2018).
Aspergillus tubingensis, as a valuable deep-sea-derived fungus needs to be further explored, is extremely rich in secondary metabolites (Koch et al., 2014). At present, anthraquinones, alkaloids, terpenoids and other compounds have been isolated from A. tubingensis, and many of the secondary metabolites have the activities of anticancer, antibacterial, anti-inflammatory and antiviral, which have a certain potential as drugs (Carboue et al., 2019; Ottoni et al., 2019). Terpenoids, which have a wide range of sources and varieties, are one of the hot anti-cancer drugs currently studied (Batool et al., 2021). There are many mechanisms of these drugs against cancer, among which the inhibition of tumor angiogenesis to inhibit the growth and metastasis of tumor cells is one of the hot research directions at present (Sun et al., 2021).
Terpenoids refer to derivatives with (C5H8)n general formula, oxygen content and different saturation levels, which can be regarded as a class of natural compounds linked in various ways by isoprene or isopentane (Hillier and Lathe, 2019). Although terpenoids are not the dominant components in A. tubingensis, they play an important role among the active ingredients because of their anticancer, antiviral and anti-inflammatory activities. It was reported that five terpenoids of 20-norisopimarane were isolated from Aspergillus from deep-sea sediments in the South China Sea, which showed significant antibacterial activity against Fusarium graminearum (Li et al., 2016). Furthermore, a new indole diterpene Penicindopene A was isolated from Penicillium YPCMAC1 from deep sea of western pacific, which showed moderate cytotoxicity to A549 and HeLa cell lines (Liu et al., 2019). Subsequently, two unique phenol-sesquiterpenoids, phomeroid A-B, were isolated from Phomopsis tersa FS441 from deep-sea sediment samples in the Indian Ocean, which showed moderate inhibitory activity against human glioblastoma SF-268, breast cancer MCF-7, liver cancer HepG-2 and lung cancer A549 (Chen et al., 2020). The above studies indicated that more and more novel chemical structures derived from medical microorganisms have been discovered, with the development of deep-sea microbial sample collection, separation and purification technology and compound structure analysis technology, which is beneficial to the excavation of medicala fungal resources (Li et al., 2015).
Even so, few studies have investigated the biosynthetic pathway of anticancer drug terpenoid, and it is becoming more and more urgent to investigate the hereditary information or functional genes of A. tubingensis by omics sequencing technology (Lin et al., 2019). Therefore, the functional genes involved in the biosynthetic pathway can be obtained by genome sequencing analysis, and the biological processes in different states can be revealed (Xiong and Zhao, 2018). In the present study, to better understand the molecular factors and their regulatory genes involved in accumulation of terpenoid, the genomic profiles of A. tubingensis were analyzed. We gain insights into the terpenoid accumulation mechanism of A. tubingensis, particularly the functional genes and enzymes involved in terpenoid biosynthesis. Physiological observations such as growth and terpenoid biosynthesis were linked to genomic data obtained by genome sequencing. These results would provide novel insight into understanding the molecular mechanisms of anticancer drug terpenoid accumulation and aid in understanding its biosynthesis, and developing future studies on the metabolic regulation of A. tubingensis.