Abstract
BackgroundAmong the common preventable cancers of women, cervical cancer has the highest morbidity. It is curable if detected at an early stage. However, reliable diagnostic and prognostic markers, which relate to physiologic and pathologic regulation of cervical cancer, are not available. In this study, one such potential marker, ZBTB28, was evaluated for its potential usefulness in cervical cancer assessment.MethodsPublic database analysis, reverse-transcription polymerase chain reaction (PCR), and methylation-specific PCR were employed to analyze ZBTB28 expression and promoter methylation. The importance of ZBTB28 in cervical cancer cells was assessed by cellular and molecular analysis in vitro and in vivo.ResultsThis study assessed the anti-tumor effects of the transcription factor, ZBTB28, which is often silenced in cervical cancer due to CpG methylation of its promoter. We found ZBTB28 to directly affect cervical cancer cell proliferation, apoptosis, autophagy, and tumorigenesis. Also, it increased cancer cell chemosensitivity to Paclitaxel, Cisplatin, and 5-fluorouracil. Ectopic ZBTB28 expression inhibited the growth of cervical cancer xenografts in nude mice. Furthermore, electron microscopy demonstrated ZBTB28 to induce autophagosomes in cervical cancer cells. ZBTB28 induced cellular autophagy by the degradation of Bcl-XL, reduction of the Bcl-XL-BECN1 complex, and by interaction with the autophagy-related gene FIP200. ZBTB28-induced autophagy of cervical cancer cells was shown to mediate cellular apoptosis through the regulation of FIP200.ConclusionThese findings identify ZBTB28 as a tumor suppressor gene that can induce autophagy-related apoptosis in cervical cancer cells. As such, ZBTB28 may be a target for the treatment of uterine-cervical carcinoma. Further, ZBTB28 promoter methylation analysis may offer a new objective strategy for cervical cancer screening.
Highlights
Among the common preventable cancers of women, cervical cancer has the highest morbidity
Zinc-finger and BTB/POZ domain-containing family protein 28 (ZBTB28) is down-regulated by CpG methylation in cervical cancer cells and tissues We have previously shown that the transcription factor ZBTB28 was a tumor suppressor molecule, which was widely expressed in normal tissues and significantly down-regulated in a variety of cancer types [7]
ZBTB28 expression was silenced in CaSki and HeLa cells, further methylation-specific polymerase chain reaction (PCR) (MSP) analysis has revealed that the methylation of ZBTB28 promoter was correlated with its down-regulation (Fig. 1a)
Summary
Among the common preventable cancers of women, cervical cancer has the highest morbidity. It is curable if detected at an early stage. It is well known that the development of cervical cancer is a multi-step carcinogenic process, which is a consequence of the activation of multiple oncogenes and the inactivation of tumor suppressor genes [2]. To improve outcomes for cervical cancer patients, it is essential to identify effective early prognostic biomarkers. ZBTB28 has been found in a variety of human tumors and is down-regulated by promoter methylation This tumor suppressor gene produces anti-cancer effects by inhibition of cellular proliferation, viability, invasion, and migration, as well as the promotion of apoptosis [6, 7]. We show for the first time, by transmission electron microscopy, that overexpression of ZBTB28 induces autophagosomes in the cervical cancer cell lines CaSki and HeLa
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