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Abstract
Non-Small Cell Lung Cancer (NSCLC) is responsible for the majority of deaths caused by cancer. Small C-terminal domain (CTD) phosphatases (SCP), CTDSP1, CTDSP2 and CTDSPL (CTDSPs) belong to SCP/CTDSP subfamily and are involved in many vital cellular processes and tumorigenesis. High similarity of their structures suggests similar functions. However their role in NSCLC remains insufficiently understood. For the first time we revealed the suppressor function of CTDSPs leading to a significant growth slowdown and senescence of A549 lung adenocarcinoma (ADC) cells in vitro. Their tumor-suppressive activity can be realized through increasing the proportion of the active form of Rb protein dephosphorylated at Ser807/811, Ser780, and Ser795 (P<0.05) thereby negatively regulating cancer cell proliferation. Moreover, we observed that a frequent (84%, 39/46) and highly concordant (Spearman’s rank correlation coefficient (rs) = 0.53–0.62, P≤0.01) down-regulation of CTDSPs and RB1 is characteristic of primary NSCLC samples (n=46). A clear difference in their mRNA levels was found between lung ADCs with and without lymph node metastases, but not in squamous cell carcinomas (SCCs) (P≤0.05). Based on The Cancer Genome Atlas (TCGA) data and the results obtained using the CrossHub tool, we suggest that the well-known oncogenic cluster miR-96/182/183 could be a common expression regulator of CTDSPs. Indeed, according to our qPCR, the expression of CTDSPs negatively correlates with these miRs, but positively correlates with their intronic miR-26a/b. Our results reflect functional association of CTDSP1, CTDSP2, and CTDSPL, expand knowledge about their suppressor properties through Rb dephosphorylation and provide new insights into the regulation of NSCLC growth.
Highlights
Lung cancer is the most commonly diagnosed cancer in the world, with high mortality [1]
The most significant down-regulation was observed for CTD phosphatase-like (CTDSPL), both in ADC and squamous cell carcinoma (SCC), with two-fold or greater decrease in 70 and 50% samples, respectively (Figure 1, upper panels (A,B))
CTDSPL2 did not show any tendencies in expression alterations in lung ADC but was characterized with overexpression in SCC
Summary
Lung cancer is the most commonly diagnosed cancer in the world, with high mortality [1]. The small C-terminal domain (CTD) phosphatases (SCP) – CTDSP1 (2q35), CTDSP2 (12q14.1), CTDSPL (3p22.2) and CTDSPL2 (15q15.3), belong to SCP/CTDSP subfamily of the haloacid dehalogenase (HAD) superfamily [5] These proteins contain a License 4.0 (CC BY). CTDSPs 1, 2, and L demonstrate 83–85% protein sequence homology of the central region (100–240 a.a.) and significant structural similarity of active centers (root-mean-square deviation, RMSD ∼0.6A ) [7]. Their catalytic centers have high structural similarity, implicating similar functions [8]. The members of the SCP subfamily are involved in vital biological processes, which are often disrupted in cancer
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