SF3B4 Depletion Retards the Growth of A549 Non-Small Cell Lung Cancer Cells via UBE4B-Mediated Regulation of p53/p21 and p27 Expression

Abstract

Splicing factor B subunit 4 (SF3B4), a component of the U2-pre-mRNA spliceosomal complex, contributes to tumorigenesis in several types of tumors. However, the oncogenic potential of SF3B4 in lung cancer has not yet been determined. The in vivo expression profiles of SF3B4 in nonsmall cell lung cancer (NSCLC) from publicly available data revealed a significant increase in SF3B4 expression in tumor tissues compared to that in normal tissues. The impact of SF3B4 deletion on the growth of NSCLC cells was determined using a siRNA strategy in A549 lung adenocarcinoma cells. SF3B4 silencing resulted in marked retardation of the A549 cell proliferation, accompanied by the accumulation of cells at the G0/G1 phase and increased expression of p27, p21, and p53. Double knockdown of SF3B4 and p53 resulted in the restoration of p21 expression and partial recovery of cell proliferation, indicating that the p53/p21 axis is involved, at least in part, in the SF3B4-mediated regulation of A549 cell proliferation. We also provided ubiquitination factor E4B (UBE4B) is essential for p53 accumulation after SF3B4 depletion based on followings. First, co-immunoprecipitation showed that SF3B4 interacts with UBE4B. Furthermore, UBE4B levels were decreased by SF3B4 depletion. UBE4B depletion, in turn, reproduced the outcome of SF3B4 depletion, including reduction of polyubiquitinated p53 levels, subsequent induction of p53/p21 and p27, and proliferation retardation. Collectively, our findings indicate the important role of SF3B4 in the regulation of A549 cell proliferation through the UBE4B/p53/p21 axis and p27, implicating the therapeutic strategies for NSCLC targeting SF3B4 and UBE4B.

METTL3‐mediated the m6A modification of SF3B4 facilitates the development of non‐small cell lung cancer by enhancing LSM4 expression

“… 9 In addition, SF3B4 might be a diagnostic biomarker of hepatocellular carcinoma, 18 , 19 and its overexpression has been found to facilitate cell metastasis and tumorigenesis. 20 Although SF3B4 has been confirmed to be highly expressed in NSCLC tissues, 8 , 12 its role in the progression of NSCLC remains to be revealed. Consistent with the database analysis results, we identified high expression of SF3B4 in NSCLC tissues.…”

“…Studies have shown that SF3B4 expression is elevated in LUAD, and its overexpression enhances LUAD cell growth 11 . In addition, SF3B4 knockdown has been confirmed to repress NSCLC cell proliferation and cell cycle 12 . Therefore, SF3B4 has the potential to be a molecular target for NSCLC treatment, and more roles and potential molecular mechanisms of SF3B4 in the progression of NSCLC need to be further revealed.…”

“…11 In addition, SF3B4 knockdown has been confirmed to repress NSCLC cell proliferation and cell cycle. 12 Therefore, SF3B4 has the potential to be a molecular target for NSCLC treatment, and more roles and potential molecular mechanisms of SF3B4 in the progression of NSCLC need to be further revealed. By analyzing the heat map of gene expression profiles in NSCLC cells after SF3B4 knockdown in GSE222598 database, we found that Sm‐like protein 4 (LSM4) was significantly reduced by SF3B4 knockdown.…”

SF3B4 promotes Twist1 expression and clear cell renal cell carcinoma progression by facilitating the export of KLF 16 mRNA from the nucleus to the cytoplasm

“…In recent years, more and more research has been conducted on SF3b4-related diseases such as Nagel syndrome and cancer [53]. Recently, Diao et al [54] found that SF3B4 promotes ovarian cancer progression by modulating alternative splicing of RAD52 [14]. SF3B4 is also closely related to the growth of non-small cell lung cancer cells.…”

SF3B4 downregulation restrains lung adenocarcinoma tumorigenesis via 5′ alternative splicing of KAT2A

“…The expression of SF3B4 was shown to be increased in hepatocellular carcinoma compared to that in normal tissues 12 , 13 . In LUAD, Kim H reported that SF3B4 depletion slowed down the growth of LUAD cells via Ubiquitination factor E4B-mediated expression of p53/p21 and p27 14 . However, the research on the relationship between SF3B4 and LUAD is only at the beginning stage, especially on the effect and mechanism of SF3B4 alternative splicing on LUAD has not been studied well.…”