Knockdown of homeobox containing 1 increases the radiosensitivity of cervical cancer cells through telomere shortening

Abstract

Abstract. Homeobox containing 1 (HMBOX1) modulates telomere length in various types of tumor cells by binding to double-stranded telomeric DNA. There is a negative correlation between telomere length and radiosensitivity in tumor cells. In the present study, we aimed to investigate the relationship among HMBOX1, telomere and radiosensitivity in cervical cancer cells. Lentivirus-based shRNAs were used to establish stable transfected cell lines in which protein and mRNA levels of HMBOX1 were notably decreased. Knockdown of HMBOX1 increased the radiosensitivity of HeLa and C33A cells. TERT protein was also decreased while HMBOX1 was downregulated. Knockdown of HMBOX1 shortened telomere length in the HeLa cells, while TERT overexpression rescued telomere shortening in the HeLa-HMBOX1 cells. Knockdown of HMBOX1 increased the apoptosis rate, decreased radiationinduced DNA damage foci, and inhibited the expression of ATM, ATR, p-ATM, p-ATR and BRCA1 in the homologous recombination repair pathway. Our data suggest a possible role of HMBOX1 in regulating radiosensitivity in cervical cancer cells. Moreover, HMBOX1 may be a potential factor in the radiotherapy of cervical cancer. IntroductionCervical cancer is the most common malignant tumor of the female reproductive system. It is the second most commonly diagnosed cancer and the third leading cause of cancerrelated death among females in developing countries (1). Radiotherapy is the major treatment for cervical cancer. For patients with early-stage disease, radiotherapy and surgery alone have equal effects. In recent years, chemoradiotherapy has gradually become a new treatment pattern for patients with locally advanced disease. It has been demonstrated that radiotherapy plays a crucial role in the treatment of cervical cancer. However, patients who suffer pelvic recurrence account for ~70% of the cases of radiotherapy failure (2). Thus, the identification of new factors that influence radiosensitivity has important significance in cervical cancer treatment.Homeobox containing 1 (HMBOX1), a new member of the homeobox genes, was identified and isolated from the human pancreatic cDNA library. HMBOX1 was described as a transcription repressor (3). In the ALT (alternative lengthening of telomeres) cell line WI38-VA13 and telomerase-positive HeLa cells, HMBOX1 was identified as a double-stranded telomeric DNA binding protein (4) and acted as a positive regulator of telomere length (5). In U2OS (ALT cells), HMBOX1 was found to modulate telomere maintenance without influencing telomere length (6). However, the further function of HMBOX1 is not fully clear.Telomeres, nucleoprotein complexes at the end of eukaryotic chromosomes, are composed of 5'-TTAGGG-3' repeats and are maintained by telomerase. Telomeres contain protein complexes and shelterin, and play a crucial role in protecting chromosome ends from DNA damage. Moreover, telomere length may serve as a target in predicting the individual radiosensitivity of patients with cancers (7-11).However, to date, the relationship bet...

WTAP promotes osteosarcoma tumorigenesis by repressing HMBOX1 expression in an m6A-dependent manner

“…For example, high expression of HMBOX1 was observed in gastric cancer, and it was associated with the poor prognosis of gastric cancer 54 . Moreover, HMBOX1 also observed as tumor suppressor in ovarian cancer 55 and cervical cancer 56 . HMBOX1 repressed the progression of ovarian cancer via regulating cell proliferation and apoptosis 55 .…”

Regulation of telomere homeostasis and genomic stability in cancer by N 6 -adenosine methylation (m 6 A)

“…HMBOX1 has been shown to modulate telomere length in various types of tumor cells ( 22 , 23 , 31 , 32 ). It is localized at telomeres that are actively extended ( 23 ), and knockdown of HMBOX1 led to attrition of telomeres ( 32 ).…”

“…HMBOX1 has been shown to modulate telomere length in various types of tumor cells ( 22 , 23 , 31 , 32 ). It is localized at telomeres that are actively extended ( 23 ), and knockdown of HMBOX1 led to attrition of telomeres ( 32 ). Therefore, we sought to examine whether the telomere length in cancer cells can be controlled by the METTL3-HMBOX1 axis.…”

Damage-Net: A program for DNA repair meta-analysis identifies a network of novel repair genes that facilitate cancer evolution

“…Therefore, by combining datasets of differing methodologies, a more in depth understanding of the results can be obtained. Interestingly, the other genes identified in all three of the studies in this example included the HR factors BRCA2 and RPA2 alongside HMBOX1 and ZNF207, both of which have recently been showed to have roles associated with the DNA damage response [ [43] , [44] , [45] , [46] ].…”