Characterization of the role of Fhit in suppression of DNA damage

Abstract

The fragile histidine triad protein, Fhit, has a number of reported tumor suppressive functions which include signaling of apoptosis in cancer cells in vitro and in vivo, modulation of the DNA damage response, down-regulation of target oncogene expression, suppression of tumor growth in vivo, and suppression of cancer cell invasion and metastasis. Most of these functions of Fhit have been observed on exogenous re-expression of Fhit in Fhit-negative cancer cells. However, little is known about the tumorigenic changes that occur in normal or precancerous cells following loss of Fhit expression. Recently, we have shown that shortly after loss of Fhit expression, cells exhibit signs of DNA replication stress-induced DNA damage and develop genomic instability. Here, we extend these findings through investigation of different factors that affect Fhit function to prevent DNA damage. We found that Fhit activity is dependent upon a functional HIT domain and the tyrosine-114 residue, previously shown to be required for tumor suppression by Fhit. Furthermore, Fhit function was shown to be independent of exogenous and endogenous sources of oxidative stress. Finally, Fhit function was shown to be dependent upon Chk1 kinase activity, but independent of Atr or Atm kinases. Evidence suggests that Fhit and Chk1 kinase cooperate to prevent replication stress-induced DNA damage. These findings provide important and unexpected insights into the mechanism whereby loss of Fhit expression contributes to cell transformation.

FHIT promoter methylation status, low protein and high mRNA levels in patients with non-small cell lung cancer

“…In our study we found elevated FHIT expression in all NSCLC subtypes which is contrary to the results of other groups (14,23,26,31). Also, in our study, FHIT expression level in macroscopically unchanged tissue, regarded as 'normal', although surrounding the primary lesion, was elevated, when compared to calibrator RNA.…”

“…FHIT expression loss was detected frequently during the early onset of disease progression in cancer (14,23). Loss of function of the FHIT gene can lead to constitutive accumulation of high levels of intracellular diadenosine tetraphosphate and the stimulation of DNA synthesis and proliferation (25,26).…”

“…Introduction of a wild-type FHIT gene suppresses tumorigenicity and FHIT transfection in 'FHIT-lacking' human cancer cells appears to induce apoptosis and inhibit cell growth (10,11). Several investigators have shown that loss of FHIT function in preneoplastic lesions can lead to the accumulation of DNA damage and cell transformation; therefore it is defined as the guardian of the preneoplastic genome (12)(13)(14). Aberrant FHIT expression caused by truncated transcripts or promoter region hypermethylation has been found in esophageal, stomach, and colon carcinomas (7,15).…”

Common Chromosomal Fragile Sites and Cancer

“…Although Fhit -/-KO mice exhibited only a marginal increase of tumourigenesis in response to various carcinogens, crossing these mice with other disease models, such as Vhl -/-KO or Nit1 -/-KO animals, rendered full penetrance of tumour development (reviewed in [ 63 ]), suggesting a cooperative role for FHIT during tumourigenesis. Recently, Saldivar et al showed that loss of Fhit expression in precancerous lesions initiates genomic instability that may eventually facilitate malignant transformation, linking alterations at CFSs to the origin of cancer genomic instability [ 64 ]. Other examples of tumour suppressor gene loss involving CFSs, include WWOX within the FRA16D , PARK2 within the FRA6E, and CAV1 and TES within the FRA7K [ 63 ].…”

A knockdown with smoke model reveals FHIT as a repressor of Heme oxygenase 1

“…4,6,20 Recent experiments demonstrate that Fhit deficiency promotes epithelial-mesenchymal transition, that FHIT expression protects genome integrity after carcinogen treatment, and also establish a role for Fhit in mitochondrial biology. [21][22][23][24][25][26][27] Hanahan and Weinberg summarized that cancer cells are marked by the gain of 6 abnormal behaviors. 12,14,28 Genome instability and subsequent genetic alterations underlie the acquisition of the hallmarks of cancer, as successive alterations in DNA produce genotypes that confer selective advantages.…”